WO2023225626A2

WO2023225626A2 - Multi-targeting lilrb antibodies and uses thereof

Info

Publication number: WO2023225626A2
Application number: PCT/US2023/067211
Authority: WO
Inventors: Neil Gibson
Original assignee: Adanate, Inc.
Priority date: 2022-05-20
Filing date: 2023-05-19
Publication date: 2023-11-23
Also published as: WO2023225626A3

Abstract

Provided herein are compositions and methods comprising anti-LILRB antibodies that bind LILRB1, LILRB2, LILRB3, and/or LILRB5.

Description

MULTI-TARGETING LILRB ANTIBODIES AND USES THEREOF

BACKGROUND

[0001] The dynamic relationship between cancer biology and the immune system is a significant factor associated with clinical outcomes. For example, the immune response plays an important role in regulating the tumor microenvironment during cancer development. Immune cells such as T cells, B cells, and NK cells thus act as modulators and effectors of cancer progression or metastasis. However, in some instances, diseases such as cancer- and disease-causing pathogens have developed different mechanisms to evade the immune system. Accordingly, the ability to target molecules and pathways associated with immunoregulatory processes may be important for the development of cancer therapeutics.

SUMMARY

[0002] Provided herein are antibodies capable of positively modulating (e.g., activating and/or modulating or reducing inhibitory signaling) immune cells or an immune response. The antibodies described herein, in certain instances, achieve a positive modulation by targeting of multiple members of the leukocyte immunoglobulin-like receptor subfamily B (LILRB) family of proteins modulating (e.g., reducing, preventing, inhibiting) inhibitory signaling. For example, the anti-LILRB antibodies provided and described herein include multi-specific antibodies that bind LILRB1, LILRB2, LILRB3, and/or LILRB5. Not all types of immune cells express each of LILRB1, LILRB2, LILRB3, and/or LILRB5 and thus, in certain instances, high affinity binders of LILRB1, LILRB2, LILRB3, and/or LILRB5, such as the anti-LILRB antibodies described herein, demonstrate advantages over monospecific LILRB binders in that the multi-specific anti- LILRB antibodies are able to positively modulate a diverse range of immune cell types (e.g., T cells, B cells, macrophages, NK cells, etc.).

[0003] Provided herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110;

(b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140;

(e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or

(I) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160.

[0004] Also provided herein are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210;

(b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220;

(c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240;

(e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250; and/or

(f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260.

[0005] Further provided are Provided herein are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310;

(b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320;

(c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and/or

(f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360.

[0006] Provided herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDRI) comprising an amino acid sequence set forth in SEQ ID NO: 410;

(b) a heavy chain complementarity' determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420;

(c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440;

(e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450; and/or

(I a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460.

[0007] Also provided are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDRI) comprising an amino acid sequence set forth in SEQ ID NO: 510;

(b) a heavy chain complementarity' determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520;

(c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540;

(e) a light chain complementarity determining region 2 (L-CDR2) comprising an ammo acid sequence set forth in SEQ ID NO: 550; and/or

(I a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0008] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof binds to LILRB1, LILRB2, LILRB3, and/or LILRB5. In some embodiments, the anti-LILRB antibody or antigen binding fragment thereof binds to a combination of LILRB1 and LILRB2, LILRRB1 and LILRB3, LILRRB1 and LILRB5, LILRRB2 and LILRB5, LILRRB3 and LILRB5, and/or LILRB2 and LILRB3. In some embodiments, the anti-LILRB antibody or antigen binding fragment thereof binds to LILRB1, LILRB2, LILRB3, and LILRB5.

[0009] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof comprise: a heavy chain framework region 1 (H-FR1), a heavy chain framework region 2 (H-FR2), a heavy chain framework region 3 (H-FR3), and a heavy chain framework region 4 (H-FR4); and a light chain framework region 1 (L-FR1), a light chain framework region 2 (L-FR2), a light chain framework region 3 (L-FR3), and a light chain framework region 4 (L-FR4).

[0010] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises: the H-FR1, the H-FR2, the H-FR3, and the H-FR4 comprise an amino acid sequence having at least about 70% identity to the H-FR1, the H-FR2, the H-FR3, and the H-FR4 of any one of SEQ ID NOs: 101 or 170-173; and/or the L-FR1, L-FR2, L- FR3, and L-FR4 comprise an amino acid sequence having at least about 70% identity to the L-FR1, the L-FR2, the L-FR3, and the L-FR4 of any one of SEQ ID NOs: 102 or ISO- 183.

[0011] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises: the H-FR1, the H-FR2, the H-FR3, and the H-FR4 comprise an amino acid sequence of the H-FR1 , the H-FR2, the H-FR3, and the H-FR4 of any one of SEQ ID NOs: 101 or 170-173; and/or the L-FR1, L-FR2, L-FR3, and L-FR4 comprise an amino acid sequence of the L-FR1, the L-FR2, the L-FR3, and the L-FR4 of any one of SEQ ID NOs: 102 or 180-183.

[0012] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB binding fragments thereof further comprise: a heavy chain variable region comprising the H-CDR1, H-CDR2, and H-CDR3; and/or a light chain variable region comprising the L-CDR1, L-CDR2, and L-CDR3. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 101; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 102. In some embodiments, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 101 ; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 102. [0013] In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 201; and/or the light chain variable region comprises an ammo acid sequence having at least about 70% identity to SEQ ID NO: 202. In some embodiments, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 201; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 202.

[0014] In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 301; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 302. In some embodiments, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 301; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 302.

[0015] In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 401; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 402. In some embodiments, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 401; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 402.

[0016] In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 501; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 502. In some embodiments, the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 501; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 502.

[0017] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region. In some embodiments, the reduced effector function is selected from the list consisting of reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof. In some embodiments, the variant Fc region comprises SEQ ID NO: 105. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 103 and the light chain comprises SEQ ID NO: 104. [0018] Provided herein is an anti-LILRB antibody or LILRB binding fragment thereof comprising a heavy chain variable region polypeptide, the heavy chain variable region polypeptide comprising: a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230; a heavy chain complementarity determining region

1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region

2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430; or a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530.

[0019] Also provided herein is an anti-LILRB antibody or LILRB binding fragment thereof comprising a light chain variable region polypeptide, the light chain variable region comprising: a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160; a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260; a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360; a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or a light chain complementarity determining region 1 (L- CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0020] Further provided are compositions comprising an immune cell and an antileukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, LILRB3, and LILRB5. In some embodiments, the immune cell is a monocyte or lymphocyte. In some embodiments, the immune cell is selected from the group consisting of: (i) a T cell, (ii) a B cell, (iii) an NK cell, (iv) a macrophage, and (v) any combination of the T cell, the B cell, the NK cell, and the macrophage.

[0021] Also provided are compositions comprising a plurality of cells and an antileukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, LILRB3, and LILRB5, the plurality of cells comprising one or more immune cells. In some embodiments, the one or more immune cells are selected from the group consisting of: (i) monocytes, (ii) lymphocytes, and (iii) both monocytes and lymphocytes. In some embodiments, the one or more immune cells are selected from the group consisting of: (i) T cells, (ii) B cells, (iii) NK cells, (iv) macrophages, and (v) any combination of T cells, B cells, NK cells, and macrophages. In some embodiments, the plurality of cells are obtained from an individual. In some embodiments, the plurality of cells are within or derived from a blood sample or a PBMC sample. In some embodiments, the anti-leukocyte immunoglobulin- like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof binds LILRB1, LILRB2, LILRB3, and LILRB5 in an ELISA. In some embodiments, the anti- LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB 1, LILRB2, LILRB3, and LILRB5 in an ELISA with a reference antibody comprising: a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region

1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region

2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region

1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region

2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region

1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region

2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0022] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises the anti-LILRB antibody or LILRB binding fragment thereof described and embodied herein.

[0023] Provided are methods of inhibiting (e.g., reducing) and/or preventing an interaction between leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) molecule and a major histocompatibility complex class I (HLA) molecule, the method comprising contacting the LILRB2 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, LILRB3, and/or LILRB5. [0024] Also provided are methods of inhibiting (e.g., reducing) and/or preventing an interaction between a leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) molecule and a major histocompatibility complex class I (HLA) molecule, the method comprising contacting the LILRB 1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, LILRB3, and/or LILRB5. [0025] Further provided are methods of inhibiting (e.g., reducing) and/or preventing an interaction between leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) molecule or a LILRB2 molecule and a major histocompatibility complex class I (HLA), the method comprising contacting the LILRB 1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB3. [0026] Provided herein are methods of inhibiting (e.g., reducing) and/or preventing an interaction between leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) molecule and a LILRB2 molecule and a major histocompatibility complex class I (HL A) molecule, the method comprising contacting the LILRB1 molecule with an anti- LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, LILRB3, and/or LILRB5.

[0027] In some embodiments, inhibiting (e.g., reducing) and/or preventing is measured by ELISA or a cell-based assay (e.g., as described herein). In some embodiments, the major histocompatibility complex, class I protein is selected from the list consisting of: (i) HLA-G, (ii) HLA-A, and (iii) both HLA-G and HLA-A. In some embodiments, the LILRB 1 or LILRB2 is expressed on the surface of a cell. In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is selected from the group consisting of: (i) a monocyte, (ii) a lymphocyte, and (iii) both the monocyte and lymphocyte. In some embodiments, the cell is selected from the group consisting of: (i) a T cell, (ii) a B cell, (iii) an NK cell, (iv) a macrophage, and (v) any combination of the T cell, the B cell, the NK cell, and the macrophage. In some embodiments, the cell is in an individual.

[0028] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof binds LILRB1, LILRB2, LILRB3, and/or LILRB5 in an ELISA. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB1 , LILRB2, LILRB3, and/or LILRB5 in an ELISA with a reference antibody comprising: a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360; a heavy chain complementarity determining region 1 (H-CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or a heavy chain complementarity determining region 1 (H- CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560. [0029] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises: a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360; a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or a heavy chain complementarity determining region 1 (H- CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560. In certain embodiments, the anti-LILRB antibody or LILRB binding fragment thereof is ADA-011.

[0030] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises the anti-LILRB antibody or LILRB binding fragment thereof described and embodied herein. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region. In some embodiments, the reduced effector function is selected from the list consisting of reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof. In some embodiments, the variant Fc region comprises SEQ ID NO: 105.

[0031] Also provided and described herein are anti-leukocyte immunoglobulm-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence NPYXiGG, wherein Xi is an H or N; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB-1, LILRB-2, LILRB-3, and/or LILRB-5.

[0032] Further provided and described herein are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 112; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence VX1NPYX2GGSX3, wherein Xi is an I or S, X2 is an H or N, and X3 is an S or T; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 132; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 142; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 152; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an ammo acid sequence set forth in SEQ ID NO: 162, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB-1, LILRB-2, LILRB-3, and/or LILRB-5.

[0033] Provided and described herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 113; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence VX1NPYX2GGSX3YKX4KFKG, wherein Xi is an I or S, X2 is an H or N, X3 is an S or T, and Xi is an Q or E; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 133; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 143; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 153; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 163. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB- 1, LILRB-2, and/or LILRB-3.

[0034] Provided and described herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 114; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence WX0GVX1NPYX2GGSX3YKX4KFKG, wherein Xo is an I or M, Xi is an I or S, X2 is an H or N, X3 is an S or T, and X4 is an Q or E; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence XiRRAQTGPYFD, wherein Xi is an I or S; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 144; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 154; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 164, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB- binding fragments thereof binds LILRB-1, LILRB-2, LILRB-3, and/or LILRB-5.

[0035] Provided and described herein are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 115; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence X1NPYX2GGS, wherein Xi is an I or S, and X2 is an H or N; (c) a heavy chain complementarity determining region 3 (H- CDR3) comprising an amino acid sequence XiRRAQTGPYFDY, wherein Xi is an I or S; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 145; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 155; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 165, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB-1, LILRB-2, LILRB-3, and/or LILRB-5. In some embodiments, binding of the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof to LILRB-1, LILRB-2, LILRB- 3, and/or LILRB-5 is measured by ELISA or a cell-binding assay.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0037] FIG. 1 shows the generation and identification of anti-LILRB antibodies that bind LILRB1 , LILRB2, and LILRB3

[0038] FIGs. 2A and 2B shows binding of an anti-LILRB antibody to LILRB 1 and LILRB2 proteins

[0039] FIGs. 3A and 3B shows activation of immune cell function (e.g., IFN-gamma production) by an anti-LILRB antibody that binds LILRB 1, LILRB2, and LILRB3 in a MLR assay.

[0040] FIGs. 4A, 4B, 4C, 4D, 4E, 4F, 4G, 4H, and 41 shows activation of immune cell proliferation (e g., T cells) by an anti-LILRB antibody that binds LILRB 1, LILRB2, and LILRB3.

[0041] FIGs. 5A and 5B shows LILRB2 domain binding.

[0042] FIGs. 6A, 6B, 6C, 6D, 6E, 6F, and 6G shows an anti-LILRB antibody that binds LILRB 1, LILRB2, and LILRB3 inhibits HLA-G from binding LILRB and reduces the suppression of T cells, B cells, and NK cells. [0043] FIGs. 7A and 7B shows data demonstrating induction of NKL cell killing of cancer cells by an anti-LILRB antibody that binds LILRB1, LILRB2, and LILRB3.

[0044] FIGs. 8A and 8B shows data demonstrating that anti-LILRB antibodies that bind LILRB1, LILRB2, and LILRB3 promotes and/or facilitates the PBMC-mediated killing of tumor cells.

[0045] FIGS. 9A and 9B show ELISA binding data for ADA-011 binding to LILRB family and LIRLA family respectively.

[0046] FIG. 10 provides dose titration data for ADA-011 binding with LILRB family.

[0047] FIG. 11 shows the binding of ADA-011 as compared to monospecific antibodies of LILRB1, LILRB2, LILRB3, and LILRB4 on classical monocytes.

[0048] FIG. 12 shows the binding of ADA-011 as compared to monospecific antibodies of LILRB 1, LILRB2, LILRB3, and LILRB4 on CD8+ T-cells.

[0049] FIG. 13 shows the binding of ADA-011 as compared to monospecific antibodies of LILRB1, LILRB2, LILRB3, and LILRB4 on NK cells.

[0050] FIG. 14 demonstrates domain structure and lists proposed ligands of the Human LILRBs and their Mouse Counterparts.

[0051] FIG. 15 is a schematic representation of ADA-011.

[0052] FIG. 16 provides data for comparison of the protein amino acid identity across the extracellular domain of human LILRA1, A3, Bl, B2, and B3 and the closest cynomolgus monkey LILR Sequences to which ADA-011 binds.

[0053] FIG. 17 provides data for comparison of the binding of ADA-01 1 to human and cynomolgus monkey PBMCs.

[0054] FIG. 18 provides summary of the protein expression of the LILR family members across multiple immune cells.

[0055] FIG. 19 provides for data for binding of ADA 011 to monocytes isolated from two different human PBMC donors.

[0056] FIG. 20 provides for data for binding of ADA 011 to B cells, T cells and NK Cells Isolated from a Human PBMC Donor

[0057] FIG. 21 provides data pertaining to enhancement of LPS induced production of TNF-a in Monocytes Differentiated into Macrophages from Multiple PBMC Donors.

[0058] FIG. 22 provides data demonstrating that ADA Oi l treatment enhances LPS induced TNF-alpha production and reverses HLA-G suppression of LPS induced TNF- alpha production. [0059] FIG. 23 provides data demonstrating that ADA-011 treatment reverses HLA-G treated MDSC suppression of CD3/CD28 stimulation of CD8+ T cell proliferation.

[0060] FIG. 24 provides data demonstrating that ADA-011 treatment reverses HLA-G suppression of IFNy production in a mixed lymphocyte reaction.

[0061] FIG. 25 provides data pertaining to characterization of LILRB1 expression and ADA-011 binding to NKL cells.

[0062] FIG. 26 provides data demonstrating that ADA-011 enhances the NK Cell mediated killing of PLC/PRF/5 Liver Cancer Cells (Left Panel) and KMS27 Myeloma Cells (Right Panel).

[0063] FIG. 27 provides in vivo antitumor activity of 9C9.E6 (ADA 011 parental antibody shown in blue) in a JEG-3/PBMC Admixed Mouse Model.

FIG. 28 provides data that ADA-011 enhances the NK cell mediated killing of PLC/PRF/5 Liver Cancer Cells In Vivo.

DETAILED DESCRIPTION

Anti-LILRB Antibodies

[0064] Provided herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof that bind LILRB1 LILRB2, LILRB3, and/or LILRB5. In some embodiments the anti-LILRB antibodies or LILRB- binding fragments thereof bind LILRB1 and LILRB2. In some embodiments the anti- LILRB antibodies or LILRB-binding fragments thereof bind LILRB 1 and LILRB3. In some embodiments the anti-LILRB antibodies or LILRB-binding fragments thereof bind LILRB2 and LILRB3. In some embodiments the anti-LILRB antibodies or LILRB- binding fragments thereof bind LILRB 1 and LILRB5. In some embodiments the anti- LILRB antibodies or LILRB-binding fragments thereof bind LILRB2 and LILRB5. In some embodiments the anti-LILRB antibodies or LILRB-binding fragments thereof bind LILRB3 and LILRB5. In some embodiments the anti-LILRB antibodies or LILRB- binding fragments thereof bind LILRB1, LILRB2, LILRB3, and/or LILRB5.

Anti-LILRB Antibody CDRs and Variable Domains

[0065] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 70% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 70% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102.

[0066] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 111; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 121; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 131 ; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 141; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 151 ; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 161. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulm-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102.

[0067] In some embodiments, the anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 112; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 122; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 132; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 142; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 152; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 162. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102.

[0068] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 113; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 123; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 133, (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 143; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 153; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 163. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102.

[0069] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 114; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 124; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 134; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 144; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 154; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 164. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an ammo acid sequence as set forth in SEQ ID NO: 102.

[0070] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 115; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 125; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 135; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 145; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 155; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 165. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102.

[0071] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 201 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 202.

[0072] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 211; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 221; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 231 ; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 241; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 251 ; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 261. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 201 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 202.

[0073] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 212; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 222; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 232; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 242; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 252; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 262. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 201 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 202.

[0074] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 213; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 223; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 233; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 243; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 253; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 263. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 201 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-bindmg fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 202. In certain embodiments, the anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB-binding fragment is ADA-011.

[0075] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 214; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 224; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 234; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 244; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 254; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 264. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 201 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 202.

[0076] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1 ) comprising an amino acid sequence set forth in SEQ ID NO: 215; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 225; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 235; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 245; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 255; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 265. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 201 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 202. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 201; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 202.

[0077] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 301 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 302.

[0078] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 311; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 321; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 331 ; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 341; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 351 ; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 361. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 301 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 302.

[0079] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 312; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 322; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 332; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 342; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 352; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 362. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 301 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulm-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 302.

[0080] In some embodiments, the anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 313; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 323; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 333; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 343; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 353; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 363. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 301 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 302.

[0081] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 314; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 324; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 334, (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 344; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 354; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 364. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 301 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 302.

[0082] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 315; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 325; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 335; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 345; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 355; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 365. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 301 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 301; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 302. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 301; and (b) a light chain variable region comprising an ammo acid sequence as set forth in SEQ ID NO: 302.

[0083] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 402.

[0084] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 411; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 421; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 431 ; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 441; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 451 ; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 461. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 402.

[0085] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 412; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 422; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 432; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 442; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 452; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 462. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 402.

[0086] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 413; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 423; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 433; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 443; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 453; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 463. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 402.

[0087] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 414; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 424; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 434; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 444; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 454; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 464. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-bindmg fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 402.

[0088] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 415; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 425; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 435; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 445; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 455; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 465. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 401 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulm-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 402. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 401; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 402.

[0089] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 501 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 501; and (b) a light chain variable region comprising an ammo acid sequence as set forth in SEQ ID NO: 502.

[0090] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 511; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 521; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 531 ; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 541; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 551 ; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 561. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 501 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulm-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 502. [0091] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 512; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 522; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 532; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 542; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 552; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 562. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 501 ; and (b) a light chain variable region comprising an ammo acid sequence having about 80% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 501; and (b) a light chain variable region comprising an ammo acid sequence as set forth in SEQ ID NO: 502.

[0092] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 513; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 523; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 533; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 543; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 553; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 563. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 501 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 502.

[0093] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1 ) comprising an amino acid sequence set forth in SEQ ID NO: 514; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 524; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 534; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 544; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 554; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 564. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 501 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 502.

[0094] In some embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 515; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 525; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 535; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 545; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 555; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 565. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 501 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 502. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 501; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 502.

[0095] Also provided herein anti-LILRB antibodies or LILRB binding fragments thereof comprising a heavy chain variable region polypeptide, the heavy chain variable region comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130;

(b) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230;

(c) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330;

(d) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430; or

(e) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530.

[0096] An anti-LILRB antibody or LILRB binding fragment thereof comprising a light chain variable region polypeptide, the light chain variable region comprising:

(a) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160;

(b) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260;

(c) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an ammo acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or

(e) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0097] Further provided are compositions comprising an immune cell (e.g., from an ex- vivo sample, PMBC, leukopack, an isolated immune cell, etc.) and an anti-LILRB antibody, wherein the LILRB antibody binds LIRB1, LILRB2, and LILRB3. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0098] Also provided are compositions comprising an anti-LILRB antibody, wherein the anti-LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB1, LILRB2, and LILRB3 in an ELISA with a reference antibody comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160;

(b) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260;

(c) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360;

(d) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or

(e) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0099] Also provided and described herein are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-bindmg fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence NPYXiGG, wherein Xi is an H or N; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB-1, LILRB-2, and/or LILRB-3.

[0100] Further provided and described herein are anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 112; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence VX1NPYX2GGSX3, wherein Xi is an I or S, X2 is an H or N, and X3 is an S or T; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 132; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 142; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 152; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 162, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB-1 , LILRB-2, and/or LILRB- 3.

[0101] Provided and described herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 113; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence VX1NPYX2GGSX3YKX4KFKG, wherein Xi is an I or S, X2 is an H or N, X3 is an S or T, and X4 is an Q or E; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 133; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 143; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 153; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 163. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 101 ; and (b) a light chain variable region comprising an amino acid sequence having about 80% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence having about 90% or greater sequence identity to SEQ ID NO: 102. In certain embodiments, the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprise: (a) a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 101; and (b) a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 102, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB- 1, LILRB-2, and/or LILRB-3.

[0102] Provided and described herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 1 14; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence WX0GVX1NPYX2GGSX3YKX4KFKG, wherein Xo is an I or M, Xi is an I or S, X₂ is an H or N, X3 is an S or T, and Xi is an Q or E; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence XiRRAQTGPYFD, wherein Xi is an I or S; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 144; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 154; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 164, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB- binding fragments thereof binds LILRB-1, LILRB-2, and/or LILRB-3.

[0103] Provided and described herein are anti -leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 115; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence X1NPYX2GGS, wherein Xi is an I or S, and X2 is an H or N; (c) a heavy chain complementarity determining region 3 (H- CDR3) comprising an amino acid sequence XiRRAQTGPYFDY, wherein Xi is an I or S; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 145; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 155; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 165, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibodies or LILRB-binding fragments thereof binds LILRB-1, LILRB-2, and/or LILRB-3.

[0104] An antibody is used in the broadest sense, and generally encompasses and/or refer to various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-bmding activity. In some embodiments, an antibody or antibodies include intact antibodies and functional (antigenbinding) antibody fragments thereof, including fragment antigen binding (Fab) fragments, F(ab’)2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), and single domain antibodies (e g., sdAb, sdFv, nanobody) fragments. In some embodiments, an antibody or antibodies include genetically engineered and/or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, tandem tri-scFv. In some embodiments, an antibody or antibodies encompass functional antibody fragments thereof. In some embodiments, an antibody or antibodies encompasses intact or full- length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD. The antibody can comprise a human IgGl constant region. The antibody can comprise a human IgG4 constant region. In some embodiments, an antibody or antibodies include , but is not limited to, full-length and native antibodies, as well as fragments and portion thereof retaining the binding specificities thereof, such as any specific binding portion thereof including those having any number of, immunoglobulin classes and/or isotypes (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and IgM); and biologically relevant (antigen-binding) fragments or specific binding portions thereof, including but not limited to Fab, F(ab’)2, Fv, and scFv (single chain or related entity). A monoclonal antibody is generally one within a composition of substantially homogeneous antibodies; thus, any individual antibodies comprised within the monoclonal antibody composition are identical except for possible naturally occurring mutations that can be present in minor amounts. A monoclonal antibody can comprise a human IgGl constant region or a human IgG4 constant region.

[0105] A native antibody generally encompasses and/or refers to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C- terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (K) and lambda (X), based on the amino acid sequence of its constant domain.

[0106] A full-length antibody, intact antibody, and whole antibody are interchangeable, and generally include and/or refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0107] A human consensus framework generally encompasses and/or refers to a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91- 3242, Bethesda MD (1991), vols. 1-3 In one embodiment, for the VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for the VH, the subgroup is subgroup III as in Kabat et al., supra. A humanized antibody encompasses and refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human framework regions (FRs). In some embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally encompasses at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0108] A complementarity determining region or CDR, which are synonymous with hypervariable region or HVR, generally include and/or refer to regions of an antibody which are hypervariable in sequence and/or form structurally defined loops (hypervariable loops) and/or contain the antigen-contacting residues (antigen contacts). In some embodiments, complementarity determining regions or CDRs generally include and refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and/or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3).

[0109] A framework region or FR generally includes and/or refers to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). In some embodiments, the framework regions are defined by the non-CDR sequences of a variable region sequence. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody -antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(l):55-77 (“IMGT” numbering scheme); Honegger A and Pliickthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho” numbering scheme); and Whitelegg NR and Rees AR, “WAM: an improved algorithm for modelling antibodies on the WEB,” Protein Eng. 2000 Dec;13(12):819-24 (“AbM” numbering scheme. In certain embodiments, the CDRs of the antibodies described herein can be defined by a method selected from Kabat, Chothia, IMGT, Aho, AbM, or combinations thereof. In some embodiments, the CDRs and FRs are defined by and/or according to a Kabat numbering scheme. In some embodiments, the CDRs and FRs are defined by and/or according to a Chothia numbering scheme. In some embodiments, the CDRs and FRs are defined by and/or according to a IMGT numbering scheme. In some embodiments, the CDRs and FRs are defined by and/or according to an EU numbering scheme.

[0110] The boundaries of a given CDR or FR, in certain instances, vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

[0111] Fc region generally encompasses and/or refers to a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxylterminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest , 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0112] A human antibody generally encompasses and/or refers to an antibody which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigenbinding residues. [0113] An acceptor human framework region generally encompasses and/or refers to a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework “derived from” a human immunoglobulin framework or a human consensus framework can comprise the same amino acid sequence thereof, or it can contain amino acid sequence changes. In some embodiments, the number of amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0114] A variable region or variable domain generally encompasses and/or refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs (See e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91(2007)). A single VH or VL domain can be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively (See e g. , Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0115] Affinity generally encompasses and/or refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, binding affinity generally encompasses and refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described throughout.

[0116] An affinity matured antibody generally encompasses and/or refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.

[0117] Binding and a determination of binding can be readily determined by methods known within the art (e.g., ELISA, surface plasmon resonance, bio-layer interferometry, isothermal calorimetry, etc.). In some embodiments, binding is determined by ELISA. In some embodiments, binding comprising a KD less than, e.g., 10^A-5 M (10 pM) as measured by surface plasmon resonance, bio-layer interferometry, or isothermal calorimetry. In some embodiments, binding comprising a KD less than, e g., 10^A-6 M (1 pM) surface plasmon resonance, bio-layer interferometry, or isothermal calorimetry. In some embodiments, binding comprising a KD less than, e.g., 10^A-7 M (100 nM) surface plasmon resonance, bio-layer interferometry, or isothermal calorimetry.

[0118] An antibody that binds to the same epitope as a reference antibody encompasses and/or refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more. An exemplary competition assay encompasses assays known in the art and the binding assays described herein.

[0119] A chimeric antibody generally encompasses and/or refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. 1 The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), e.g., IgGi, IgG2, IgGs, IgGr, IgAi, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, d, e, g, and m, respectively.

[0120] A monoclonal antibody generally encompasses and/or refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. In some embodiments, the modifier monoclonal indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure can be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phagedisplay methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0121] An isolated antibody generally encompasses and/or refers to an antibody that has been separated from a component of its natural environment. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC).

[0122] In certain embodiments, the antibody comprises one or more naturally occurring amino acids. In certain embodiments, the antibody consists of naturally occurring amino acids. As used herein, naturally occurring amino acids include and/or refer to amino acids which are generally found in nature and are not manipulated by man. In certain instances, naturally occurring includes and/or further refers to the 20 conventional amino acids: alanine (A or Ala), cysteine (C or Cys), aspartic acid (D or Asp), glutamic acid (E or Glu), phenylalanine (F or Phe), glycine (G or Gly), histidine (H or His), isoleucine (I or He), lysine (K or Lys), leucine (L or Leu), methionine (M or Met), asparagine (N or Asn), proline (P or Pro), glutamine (Q or Gin), arginine (R or Arg), serine (S or Ser), threonine (T or Thr), valine (V or Vai), tryptophan (W or Trp), and tyrosine (Y or Tyr).

[0123] In some embodiments, the antibody comprises a variant sequence of the antibody. In certain instances, amino acid substitutions can be made in the sequence of any of the antibodies described herein, without necessarily decreasing or ablating its activity (as measured by, e.g., the binding or functional assays described herein). Accordingly, in some embodiments, the variant sequence comprises one or more amino acid substitutions. In some embodiments, the variant sequence comprises one or more substitutions in one or more CDRs. In certain embodiments, the variant sequence comprises one amino acid substitution. In certain embodiments, the variant sequence comprises two amino acid substitutions. In certain embodiments, the variant sequence comprises three amino acid substitutions. In certain instances, substitutions include conservative substitutions (e.g., substitutions with amino acids of comparable chemical characteristics). In certain instances, a non-polar amino acid can be substituted and replaced with another non-polar amino acid, wherein non-polar amino acids include alanine, leucine, isoleucine, valine, glycine, proline, phenylalanine, tryptophan and methionine. In certain instances, a neutrally charged polar amino acids can be substituted and replaced with another neutrally charged polar amino acid, wherein neutrally charged polar amino acids include serine, threonine, cysteine, tyrosine, asparagine, and glutamine. In certain instances, a positively charged amino acid can be substituted and replaced with another positively charged amino acid, wherein positively charged amino acids include arginine, lysine and histidine. In certain instances, a negatively charged amino acid can be substituted and replaced with another negatively charged amino acid, wherein negatively charged amino acids include aspartic acid and glutamic acid. Examples of amino acid substitutions also include substituting an L-amino acid for its corresponding D-amino acid, substituting cysteine for homocysteine or other non-natural amino acids.

[0124] In certain embodiments, the antibody comprises one or more non-natural amino acids. In certain embodiments, the antibody consists of non-natural amino acids. As used herein, non-natural amino acids and/or unnatural amino acids include and/or refer to amino acid structures that cannot be generated biosynthetically in any organism using unmodified or modified genes from any organism. For example, these include, but are not limited to, modified amino acids and/or amino acid analogues that are not one of the 20 naturally occurring amino acids (e g., non-natural side chain variant sequence amino acids), D-amino acids, homo amino acids, beta-homo amino acids, N-methyl amino acids, alpha-methyl amino acids, or. By way of further example, non-natural amino acids also include 4-Benzoylphenylalanine (Bpa), Aminobenzoic Acid (Abz), Aminobutyric Acid (Abu), Aminohexanoic Acid (Ahx), Aminoisobutyric Acid (Aib), Citrulline (Cit), Diaminobutyric Acid (Dab), Diaminopropanoic Acid (Dap), Diaminopropionic Acid (Dap), Gamma-Carboxyglutamic Acid (Gia), Homoalanine (Hala), Homoarginine (Harg), Homoasparagine (Hasn), Homoaspartic Acid (Hasp), Homocysteine (Heys), Homoglutamic Acid (Hglu), Homoglutamine (Hgln), Homoisoleucine (Hile), Homoleucine (Hleu), Homomethionine (Hmet), Homophenylalanine (Hphe), Homoserine (Hser), Homotyrosine (Htyr), Homovaline (Hval), Hydroxyproline (Hyp), Isonipecotic Acid (Inp), N aphthyl alanine (Nal), Nipecotic Acid (Nip), Norleucine (Nle), Norvaline (Nva), Octahydroindole-2-carboxylic Acid (Oic), Penicillamine (Pen), Phenylglycine (Phg), Pyroglutamic Acid (Pyr), Sarcosine (Sar), tButylglycine (Tie), and Tetrahydro- isoquinoline-3-carboxylic Acid (Tic). Such non-natural amino acid residues can be introduced by substitution of naturally occurring amino acids, and/or by insertion of nonnatural amino acids into the naturally occurring antibody sequence. A non-natural amino acid residue also can be incorporated such that a desired functionality is imparted to the apelin molecule, for example, the ability to link a functional moiety (e.g., PEG).

Anti-LILRB Antibody Variant Fc Regions

[0125] Effector functions generally include and/or refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation. In some embodiments, the antibodies described herein comprise mutations that reduce effector function.

[0126] In some embodiments, one or more amino acid modifications are introduced into the Fragment crystallizable (Fc) region of a human or humanized antibody, thereby generating an Fc region variant. An Fc region may comprise a C-terminal region of an immunoglobulin heavy chain that comprises a hinge region, CH2 domain, CH3 domain, or any combination thereof. As used herein, an Fc region includes native sequence Fc regions and variant Fc regions. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgGl , IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g., a substitution, addition, or deletion) at one or more amino acid positions.

[0127] In some embodiments, a variant Fc region comprises at least one amino acid modification in the Fc region. Combining amino acid modifications are also useful. For example, the variant Fc region may include two, three, four, five, etc. substitutions therein, e.g. of the specific Fc region positions identified herein.

[0128] In some embodiments, the antibodies described herein have a reduced effector function as compared to a human IgG. Effector functions generally refer to a biological event resulting from the interaction of an antibody Fc region with an Fc receptor or ligand. Non-limiting effector functions include Clq binding, complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g. B cell receptor), and B cell activation. In some cases, antibodydependent cell-mediated cytotoxicity (ADCC) refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing Fc receptors (e.g., natural killer cells, neutrophils, macrophages) recognize bound antibody on a target cell, subsequently causing lysis of the target cell. In some cases, complement dependent cytotoxicity (CDC) refers to lysing of target cells in the presence of complement, where the complement action pathway is initiated by the binding of Clq to antibody bound with the target.

[0129] In certain cases, it is beneficial to reduce the effector function of the antibodies described herein. In some instances, modifications in the Fc region generate an Fc variant with (a) decreased antibody-dependent cell-mediated cytotoxicity ADCC), (b) decreased complement mediated cytotoxicity (CDC), and/or (c) decreased affinity for Clq. In some embodiments, the Fc region is modified to decrease antibody dependent cellular cytotoxicity (ADCC), decrease antibody-dependent cell-mediated phagocytosis (ADCP), decrease complement mediated cytotoxicity (CDC), and/or decrease affinity for Clq by modifying one or more amino acids at the following positions: 234, 235, 236, 238, 239, 240, 241, 243, 244, 245, 247, 248, 249, 252, 254, 255, 256, 258, 262, 263, 264, 265, 267,

268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298,

299, 301, 303, 305, 307, 309, 312, 313, 315, 320, 322, 324, 325, 326, 327, 329, 330, 331,

332, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419,

430, 433, 434, 435, 436, 437, 438 or 439 (EU numbering). In some embodiments, the variant Fc region is selected from one or more of the following:

[0130] Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Pat. No. 5,500,362 and 5,821,337. Alternatively, nonradioactive assays methods may be employed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC), monocytes, macrophages, and Natural Killer (NK) cells.

[0131] In some embodiments, variant Fc regions exhibit ADCC that is reduced by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more as compared to an antibody comprising a non-variant Fc region, i.e., an antibody with the same sequence identity but for the substitution(s) that decrease ADCC (such as human TgGl ). Tn some embodiments, variant Fc regions exhibit CDC that is reduced by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70% or more as compared to an antibody comprising a non-variant Fc region, i.e., an antibody with the same sequence identity but for the substitution(s) that decrease CDC (such as human IgGl).

[0132] In certain embodiments, variant Fc regions exhibit ADCC that is reduced by about 10 % to about 100 %. In certain embodiments, variant Fc regions exhibit ADCC that is reduced by about 10 % to about 20 %, about 10 % to about 30 %, about 10 % to about 40 %, about 10 % to about 50 %, about 10 % to about 60 %, about 10 % to about 70 %, about 10 % to about 80 %, about 10 % to about 90 %, about 10 % to about 100 %, about 20 % to about 30 %, about 20 % to about 40 %, about 20 % to about 50 %, about 20 % to about 60 %, about 20 % to about 70 %, about 20 % to about 80 %, about 20 % to about 90 %, about 20 % to about 100 %, about 30 % to about 40 %, about 30 % to about 50 %, about 30 % to about 60 %, about 30 % to about 70 %, about 30 % to about 80 %, about 30 % to about 90 %, about 30 % to about 100 %, about 40 % to about 50 %, about 40 % to about 60 %, about 40 % to about 70 %, about 40 % to about 80 %, about 40 % to about 90 %, about 40 % to about 100 %, about 50 % to about 60 %, about 50 % to about 70 %, about 50 % to about 80 %, about 50 % to about 90 %, about 50 % to about 100 %, about 60 % to about 70 %, about 60 % to about 80 %, about 60 % to about 90 %, about 60 % to about 100 %, about 70 % to about 80 %, about 70 % to about 90 %, about 70 % to about 100 %, about 80 % to about 90 %, about 80 % to about 100 %, or about 90 % to about 100 %. In certain embodiments, variant Fc regions exhibit ADCC that is reduced by about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, about 90 %, or about 100 %. In certain embodiments, variant Fc regions exhibit ADCC that is reduced by at least about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, or about 90 %.

[0133] In certain embodiments, variant Fc regions exhibit CDC that is reduced by about 10 % to about 100 %. In certain embodiments, variant Fc regions exhibit CDC that is reduced by about 10 % to about 20 %, about 10 % to about 30 %, about 10 % to about 40 %, about 10 % to about 50 %, about 10 % to about 60 %, about 10 % to about 70 %, about 10 % to about 80 %, about 10 % to about 90 %, about 10 % to about 100 %, about 20 % to about 30 %, about 20 % to about 40 %, about 20 % to about 50 %, about 20 % to about 60 %, about 20 % to about 70 %, about 20 % to about 80 %, about 20 % to about 90 %, about 20 % to about 100 %, about 30 % to about 40 %, about 30 % to about 50 %, about 30 % to about 60 %, about 30 % to about 70 %, about 30 % to about 80 %, about 30 % to about 90 %, about 30 % to about 100 %, about 40 % to about 50 %, about 40 % to about 60 %, about 40 % to about 70 %, about 40 % to about 80 %, about 40 % to about 90 %, about 40 % to about 100 %, about 50 % to about 60 %, about 50 % to about 70 %, about 50 % to about 80 %, about 50 % to about 90 %, about 50 % to about 100 %, about 60 % to about 70 %, about 60 % to about 80 %, about 60 % to about 90 %, about 60 % to about 100 %, about 70 % to about 80 %, about 70 % to about 90 %, about 70 % to about 100 %, about 80 % to about 90 %, about 80 % to about 100 %, or about 90 % to about 100 %. In certain embodiments, variant Fc regions exhibit CDC that is reduced by about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, about 90 %, or about 100 %. In certain embodiments, variant Fc regions exhibit CDC that is reduced by at least about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, or about 90 %.

[0134] In some embodiments, variant Fc regions exhibit reduced effector function as compared with wild-type human IgGl. Non-limiting examples of Fc mutations in IgGl that, in certain instances, reduce ADCC and/or CDC include substitutions at one or more of positions: 231, 232, 234, 235, 236, 237, 238, 239, 264, 265, 267, 269, 270, 297, 299, 318, 320, 322, 325, 327, 328, 329, 330, and 331 in IgGl, where the numbering system of the constant region is that of the EU index as set forth by EU.

[0135] In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an N297A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an N297Q substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an N297D substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an D265A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an S228P substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an L235A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an L237A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an L234A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an E233P substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an L234V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an C236 deletion, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising a P238A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an A327Q substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising a P329A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an P329G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an L235E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an P331S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an L234F substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising a 235G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 235Q substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 235R substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 235 S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 236F substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 236R substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 237E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 237K substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 237N substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 237R substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 2381 substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238W substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 238Y substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 248A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254D substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 2541 substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254N substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254P substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254Q substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254T substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 254V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 255N substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 256H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 256K substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 256R substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 256V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 264S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 265H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 265K substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 265S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 265Y substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 267G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 267H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 2671 substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 267K substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 268K substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 269N substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 269Q substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 270A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 270G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 270M substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 270N substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 271T substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 272N substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 279F substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 279K substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 279L substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 292E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 292F substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 292G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 2921 substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 293S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 301W substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 304E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 31 IE substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 311G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 311 S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 316F substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 327T substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 328V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 329Y substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 330R substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 339E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 339L substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 3431 substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 343V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 373A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 373G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 373S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 376E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 376W substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 376Y substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 380D substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 382D substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 382P substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 385P substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 424H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 424M substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 424V substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 4341 substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 438G substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 439E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 439H substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 439Q substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440D substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440E substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440F substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440M substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440T Fc region substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising an 440V substitution, according to the EU numbering system.

[0136] In some embodiments, the variant Fc region comprises an IgGl Fc region L234A, L235E, G237A, A330S, and/or P331S by EU Numbering. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising E233P, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG4 Fc region comprising S228P and L235E. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L235E, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A and L235A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A, L235A, and G237A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A, L235A, P329G, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234F, L235E, and P331 S, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A, L235E, and G237A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A, L235E, G237A, and P331S, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A, L235A, G237A, P238S, H268A, A330S, and P331S (IgGl), according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising L234A, L235A, and P329A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising G236R and L328R, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising G237A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising F241 A, according to the EU numbering system. In some embodiments,

61 the variant Fc region comprises an IgGl Fc region comprising V264A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising D265A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising D265A and N297A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising D265A and N297G, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising D270A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising N297A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising N297G, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising N297D, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising N297Q, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising P329A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising P329G, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising P329R, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising A330L, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising P331A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgGl Fc region comprising P331S, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG2 Fc region. In some embodiments, the variant Fc region comprises an IgG4 Fc region. In some embodiments, the variant Fc region comprises an IgG4 Fc region comprising S228P, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG4 Fc region comprising S228P, F234A, and L235A, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG2-IgG4 cross-subclass (IgG2/G4) Fc region. In some embodiments, the variant Fc region comprises an IgG2-IgG3 cross-subclass Fc region. In some embodiments, the variant Fc region comprises an IgG2 Fc region comprising H268Q, V309L, A330S, and P331S, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG2 Fc region comprising V234A, G237A, P238S, H268A, V309L, A330S, and P331S, according to the EU numbering system. In some embodiments, an antibody comprises a Fc region comprising high mannose glycosylation.

[0137] In some embodiments, the variant Fc region comprises an IgG4 Fc region comprising a S228P substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG4 Fc region comprising an A330S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG4 Fc region comprising a P33 IS substitution, according to the EU numbering system.

[0138] In some embodiments, the variant Fc region comprises an IgG2 Fc region comprising an A330S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG2 Fc region comprising an P331S substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG2 Fc region comprising an 234A substitution, according to the EU numbering system. In some embodiments, the variant Fc region comprises an IgG2 Fc region comprising an 237A substitution, according to the EU numbering system.

[0139] In some embodiments, the variant Fc region comprises IgGl Fc region, and wherein the one or more mutations comprises (a) 297A, 297Q, 297G, or 297D, (b) 279F, 279K, or 279L, (c) 228P, (d) 235A, 235E, 235G, 235Q, 235R, or 235S, (e) 237A, 237E, 237K, 237N, or 237R, (f) 234A, 234V, or 234F, (g) 233P, (h) 328A, (i) 327Q or 327T,

(j) 329A, 329G, 329Y, or 329R (k) 33 IS, (1) 236F or 236R, (m) 238A, 238E, 238G, 238H, 2381, 238V, 238W, or 238Y, (n) 248A, (o) 254D, 254E, 254G, 254H, 2541, 254N, 254P, 254Q, 254T, or 254V, (p) 255N, (q) 256H, 256K, 256R, or 256V, (r) 264S, (s) 265H, 265K, 265S, 265Y, or 265A, (t) 267G, 267H, 2671, or 267K, (u) 268K, (v) 269N or 269Q, (w) 270 A, 270G, 270M, or 270N, (x) 27 IT, (y) 272N, (z) 292E, 292F, 292G, or 2921,

(aa) 293S, (bb) 301W, (cc) 304E, (dd) 311E, 311G, or 31 IS, (ee) 316F, (ff) 328V, (gg) 330R, (hh) 339E or 339L, (ii) 3431 or 343V, (jj) 373 A, 373G, or 373S, (kk) 376E, 376W, or 376Y, (11) 380D, (mm) 382D or 382P, (nn) 385P, (oo) 424H, 424M, or 424V, (pp) 4341, (qq) 438G, (rr) 439E, 439H, or 439Q, (ss) 440A, 440D, 440E, 440F, 440M, 440T, or 440V, (tt) K322A, (uu) L235E, (vv) L234A and L235A, (ww) L234A, L235A, and G237A, (xx) L234A, L235A, and P329G, (yy) L234F, L235E, and P331S, (zz) L234A, L235E, and G237A, (aaa), L234A, L235E, G237A, and P331S (bbb) L234A, L235A, G237A, P238S, H268A, A330S, and P331S, (ccc) L234A, L235A, and P329A, (ddd) G236R and L328R, (eee) G237A, (fff) F241A, (ggg) V264A, (hhh) D265A, (iii) D265A and N297A, (jjj) D265A and N297G, (kkk) D270A, (111) A330L, (mmm) P331 A or P33 IS, or (nnn) E233P, (ooo) L234A, L235E, G237A, A330S, and P331S or (ppp) any combination of (a) - (uu), per EU numbering.

[0140] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region. In some embodiments, the reduced effector function is selected from the list consisting of reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof. In some embodiments, the variant Fc region comprises SEQ ID NO: 105. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 103 and a light chain comprising SEQ ID NO: 104.

Host Cells and Nucleic Acids

[0141] Host cells, host cell lines, and/or host cell cultures are used interchangeably, and generally include and/or refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include transformants and transformed cells, which include the primary transformed cell and progeny derived therefrom without regard to the number of passages.

[0142] An isolated nucleic acid generally encompasses and/or refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid encompasses a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. An Isolated nucleic acid encoding an antibody encompasses and/or refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell. In some embodiments, provided herein is a nucleic acid sequence encoding the anti-LILRB antibodies described herein. In some embodiments, also provided is a host cell comprising the nucleic acid sequence encoding the anti-LILRB antibodies described herein. Pharmaceutical Compositions

[0143] A pharmaceutical formulation generally encompasses and/or refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0144] A pharmaceutically acceptable carrier generally encompasses and/or refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier encompasses, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0145] An effective amount of an agent, e g., a pharmaceutical formulation, generally encompasses and/or refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. A therapeutically effective amount refers to an amount of, e g., an immunotherapeutic agent (such as an immunotherapeutic antibody or composition comprising a therapeutic antibody described herein) effective to treat a disease or disorder or status in a subject (e.g., a mammal, such as a human).

[0146] A polypeptide or protein are used interchangeably, and generally encompass and/or refer to a polymer of amino acid residues, and are not limited to a minimum length. Polypeptides, including the provided antibodies and antibody chains and other peptides, e g., linkers and binding peptides, can include amino acid residues including natural and/or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some embodiments, the polypeptides can contain modifications with respect to a native or natural sequence, as long as the protein maintains the desired activity. These modifications can be deliberate, as through site-directed mutagenesis, or can be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0147] Compositions comprising the anti-LILRB antibodies of the current disclosure are included in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. In certain embodiments, the antibodies of the current disclosure are administered suspended in a sterile and/or isotonic solution. In certain embodiments, the solution comprises about 0.9% NaCl. In certain embodiments, the solution comprises about 5.0% dextrose. In certain embodiments, the solution further comprises one or more of: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and hydroxy methylaminomethane (Tris); surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and poloxamer 188; polyol/disaccharide/polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, L-Histidine/L-histidine monohydrochloride monohydrate, trehalose, and dextran 40; amino acids, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA or EGTA.

[0148] Subcutaneous formulations for administration of antibodies can comprise one or more of: buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and hydroxymethylaminomethane (Tris); surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20), and poloxamer 188; polyol/disaccharide/polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, trehalose, and dextran 40; amino acids, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA or EGTA. Additionally, a compound or molecule that relieves pain at the injection site can be included, such as hyaluronidase, for example at a concentration of from about 2,000 U/ml to about 12,000 U/ml.

[0149] In certain embodiments, the antibodies of the current disclosure are shipped/stored lyophilized and reconstituted before administration. In certain embodiments, lyophilized antibody formulations comprise a bulking agent such as, mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation can be contained in a vial comprised of glass or other suitable non-reactive material. The antibodies when formulated, whether reconstituted or not, can be buffered at a certain pH, generally less than 7.0. In certain embodiments, the pH can be between 4.5 and 6.5, 4.5 and 6.0, 4.5 and 5.5, 4.5 and 5.0, or 5.0 and 6.0.

[0150] Also described herein are kits comprising one or more of the antibodies described herein in a suitable container and one or more additional components selected from: instructions for use; a diluent, an excipient, a carrier, and a device for administration.

[0151] In certain embodiments, described herein is a method of preparing a treatment comprising admixing one or more pharmaceutically acceptable excipients, carriers, or diluents and a antibody of the current disclosure. In certain embodiments, described herein is a method of preparing a cancer treatment for storage or shipping comprising lyophilizing one or more antibodies of the current disclosure. Methods and Uses

[0152] The anti-LILRB antibodies provided and described herein can be useful for modulating immune cell function (e.g., increasing immune cell activation and/or function). In some embodiments, the anti-LILRB antibodies (e.g., anti-LILRB 1-3 antibodies) prevent and/or reduce HLA-mediated suppression of immune cells (e.g., T cell, B cells, macrophages and/or NK cells). In certain instances, antibodies that bind LILRB1, LILRB2, LILRB3, and/or LILRB5 provide an advantage in targeting different immune cell types with a single anti-LILRB antibody because different immune cell types do not express each of LILRB1, LILRB2, LILRB3, or LILRB5.

[0153] Provided herein are methods of inhibiting, reducing, and/or modulating (e.g., preventing, inhibiting, reducing, etc.) an interaction between a LILRB molecule and HLA-G or HLA-A, the methods comprising: contacting the LILRB molecule with an anti- LILRB antibody that binds LILRB 1, LILRB2, LILRB3, and LILRB5, or a LILRB-binding fragment thereof. In some embodiments, the LILRB molecule is LILRB 1, LILRB2, LILRB3, LILRB5, or a combination thereof. In certain embodiments, the LILRB molecule is LILRB 1. In certain embodiments, the LILRB molecule is LILRB2. In certain embodiments, the LILRB molecule is LILRB3. In certain embodiments, the LILRB molecule is LILRB5. In certain embodiments the LILRB molecule is expressed on the surface of a cell (e.g., an immune cell).

[0154] Also provided herein are methods of modulating (e.g., inhibiting or preventing HLA-G binding) leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) expressed on the surface of a cell, the method comprising contacting the LILRB2 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, LILRB3, and/or LILRB5. Further provided are methods of modulating leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) expressed on the surface of a cell, the method comprising contacting the LILRB 1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, LILRB3, and/or LILRB5. Provided are methods of modulating leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3) expressed on the surface of a cell, the method comprising contacting the LILRB 1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB 3.

[0155] In some embodiments, inhibiting, reducing, and/or preventing comprises a reduction in HLA-A or HLA-G binding to LILRB2. In certain embodiments, the reduction comprises at least 10% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 20% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 30% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 40% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 50% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 60% when compared to HLA-A or HLA- G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 70% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 80% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody. In certain embodiments, the reduction comprises at least 90% when compared to HLA-A or HLA-G binding to LILRB2 in the absence of the anti-LILRB antibody.

[0156] In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560. [0157] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB1, LILRB2, LILRB3, and LILRB5 in an ELISA with a reference antibody comprising:

(c) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360; (d) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or

(e) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

[0158] In some embodiments, the LILRB molecule comprises LILRB1 , LILRB2, LILRB3, or LILRB5. In certain embodiments, the LILRB molecule comprises LILRB 1. In certain embodiments, the LILRB molecule comprises LILRB2. In certain embodiments, the LILRB molecule comprises LILRB3. In certain embodiments, the LILRB molecule comprises LILRB5. In some embodiments, the LILRB molecule is located on the surface of an immune cell. In certain embodiments, the immune cell comprises a T cell (e.g., CD8+ and/or CD4+), B cell, NK cell, or a combination thereof. In some embodiments, the immune cell is in an individual. In certain embodiments, the individual is a human. In some embodiments, the immune cell is in an ex-vivo sample (e.g., PBMC or isolated cells).

[0159] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region. In some embodiments, the reduced effector function is selected from the list consisting of reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof. In some embodiments, the variant Fc region comprises SEQ ID NO: 105. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 103 and a light chain comprising SEQ ID NO: 104. In some embodiments, the cancer comprises a solid tumor.

[0160] Also provided herein are methods of inhibiting growth of a tumor (e g., mass or volume), the methods comprising: contacting an immune cell with an anti-LILRB antibody that binds LILRB1, LILRB2, LILRB3, and/or LILRB5, or a LILRB-binding fragment thereof, wherein contacting the immune cell with the anti-LILRB antibody that binds LILRB 1, LILRB2, LILRB3, and/or LILRB5, or a LILRB-binding fragment thereof, reduces or inhibits growth of the tumor. Further provided are methods of activating an anti-tumor immune response, the methods comprising contacting an immune cell with an anti-LILRB antibody that binds LILRB 1, LILRB2, LILRB3, and/or LILRB5, or a LILRB- binding fragment thereof, wherein contacting the immune cell with the anti-LILRB antibody that binds LILRB 1, LILRB2, LILRB3, and LILRB5, or a LILRB-binding fragment thereof, thereby activating the anti-tumor immune response. In some embodiments, the anti-tumor immune response comprises the release of cytokines (e.g., IL-2 or IL- 15). In some embodiments, the anti -tumor immune response comprises the proliferation of the immune cell. In certain embodiments, the immune cell is a T cell (e.g., CD8+ or CD4+), an NK cell, a B cell, or a combination thereof. In some embodiments the immune cell is in an individual

[0161] In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1 ) comprising an amino acid sequence set forth in SEQ ID NO: 410; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460. In some embodiments, the anti-LILRB antibody comprises: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550; and/or (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

(a) In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB 1, LILRB2, and LILRB3 in an ELISA with a reference antibody comprising: a heavy chain complementarity determining region 1 (H- CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160; (b) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260;

(c) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360;

[0162] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an ammo acid sequence set forth in SEQ ID NO: 160. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an ammo acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560. [0163] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region. In some embodiments, the reduced effector function is selected from the list consisting of reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof. In some embodiments, the variant Fc region comprises SEQ ID NO: 105. In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 103 and a light chain comprising SEQ ID NO: 104. In some embodiments, the cancer comprises a solid tumor. [0164] In some embodiments, the anti-LILRB antibody or LILRB binding fragment thereof is ADA-011. In certain embodiments, ADA-011 is a fully humanized immunoglobulin G1 (IgGl) monoclonal antibody with a combination of Leu234Ala and Leu235Ala (LAL A) mutations in the Fc region, which binds to human leukocyte immunoglobulin-like receptors, sub-family B (LILRB) 1, LILRB2, LILRB3, and LILRB5 receptors.

[0165] The determination of percent identity or percent similarity between two sequences can be accomplished using a mathematical algorithm. A non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403-410. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. Additional algorithms for sequence analysis are known in the art and include ADVANCE and ADAM as described in Torellis and Robotti, 1994, Comput. Appl. Biosci. 10:3-5; and FASTA described in Pearson and Lipman, 1988, Proc. Natl. Acad. Sci. USA 85:2444-8. Alternatively, sequence alignment may be carried out using the CLUSTAL algorithm (e.g., as provided in the program Clustal-omega), as described by Higgins et al., 1996, Methods Enzymol. 266:383-402.

[0166] As used herein the term individual, patient, or subject generally includes and/or refers to individuals diagnosed with, suspected of being afflicted with, or at-risk of developing at least one disease, condition, or status for which the described compositions and method are useful for treating. In certain embodiments, the individual is a mammal. In certain embodiments, the mammal is a mouse, rat, rabbit, dog, cat, horse, cow, sheep, pig, goat, llama, alpaca, or yak. In certain embodiments, the individual is a human.

[0167] As used herein, treatment or treating generally include and/or refer to a pharmaceutical or other intervention regimen used for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made. Skilled artisans will recognize that given a population of potential individuals for treatment not all will respond or respond equally to the treatment. Such individuals are considered treated.

[0168] As used herein, the words modulation and regulation can be used interchangeably herein. In some embodiments, modulation comprises a decrease and/or reduction and/or inhibition. In some embodiments, modulation comprises to an increase and/or induction and/or promotion and/or activation.

[0169] As used herein, the words comprising (and any form of comprising, such as comprise and comprises), having (and any form of having, such as have and has), including (and any form of including, such as include and includes) or containing (and any form of containing, such as contain and contains), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps. As also used herein, in any instance or embodiment described herein, comprising may be replaced with consisting essentially of and/or consisting of. used herein, in any instance or embodiment described herein, comprises may be replaced with consists essentially of and/or consists of.

[0170] As used herein, the term about in the context of a given value or range includes and/or refers to a value or range that is within 20%, within 10%, and/or within 5% of the given value or range

[0171] As used herein, the term and/or is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, A and/or B is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each were set out individually herein. [0172] As used herein, a sample includes and/or refers to any fluid or liquid sample which is being analyzed in order to detect and/or quantify an analyte. In some embodiments, a sample is a biological sample. Examples of samples include without limitation a bodily fluid, an extract, isolated cells, a solution containing proteins and/or DNA, a cell extract, a cell lysate, or a tissue lysate. Non-limiting examples of bodily fluids include urine, saliva, blood, serum, plasma, cerebrospinal fluid, tears, semen, sweat, pleural effusion, liquified fecal matter, and lacrimal gland secretion.

[0173] As used herein, LILRB1 or leukocyte immunoglobulin like receptor Bl or leukocyte immunoglobulin-like receptor subfamily B member 1 (also known as ILT2; LIR1; MIR7; CD85J; ILT-2; LIR-1; MIR-7) generally includes and refers to the receptor for class I MHC antigens. In some embodiments, LILRB1 refers to the polypeptide of UniProt Ref : Q8NHL6 (e.g., Q8NHL6-1, Q8NHL6-2, Q8NHL6-3, Q8NHL6-4, Q8NHL6-5) or NCBI Gene ID: 10859, including variants, isoforms, and haplotypes thereof.

[0174] As used herein, LILRB2 or leukocyte immunoglobulin like receptor B2 or leukocyte immunoglobulm-like receptor subfamily B member 2 (also known as ILT4; LIR2; CD85D; ILT-4; LIR-2; MIR10; MIR-10) generally includes and refers to the receptor for class I MHC antigens. In some embodiments, LILRB2 refers to the polypeptide of UniProt Ref.: Q8N423 (e.g., Q8N423-1, Q8N423-2, Q8N423-3, Q8N423- 4) or NCBI Gene ID: 10288, including variants, isoforms, and haplotypes thereof.

[0175] As used herein, LILRB3 or leukocyte immunoglobulin like receptor B3 or leukocyte immunoglobulin-like receptor subfamily B member 3 (also known as CD85A, HL9, ILT-5, ILT5, LILRA6, LIR-3, LIR3) generally includes and refers to the receptor for class I MHC antigens. In some embodiments, LILRB3 refers to the polypeptide of UniProt Ref : 075022 (e.g., 075022-1, 075022-2, 075022-3) or NCBI Gene ID: 11025, including variants, isoforms, and haplotypes thereof.

[0176] As used herein, LILRB5 or leukocyte immunoglobulin like receptor B5 or leukocyte immunoglobulin-like receptor subfamily B member 5 (also known as CD85C, LIR-8, or LIR 8) generally includes and refers to the receptor for class I MHC antigens.

EXAMPLES

Example 1 - Generation of anti-LILRB Antibodies

[0177] Full length extracellular domain constructs for LILRB proteins were synthesized and cloned into a N-terminal hlgGl expression vector. Confirmed clones were expressed in 293F cells and recombinant protein purified using protein A columns. The immunization strategy comprised parallel immunization of two mouse strains (BALB/c and SJL) with recombinant full length extracellular LILRB-Fc proteins using standard repetitive immunization at multiple sites (RIMMS) immunization procedure. Hybridomas were generated using mice with high serum titers of antibody reactive to the target immunogen. Fusions were performed, seeded into 96-well plates and hybridoma supernatants screened for binding to His-FLAG tagged LILRB1-4 proteins. An emphasis was placed on the selection of diverse cross-reactive antibody binding profiles

[0178] Based on antibody binding by ELISA, hybridomas were selected for subcloning. For each selected well of 96-well plate screening, subclones were expanded and purified for in vitro functional assays.

[0179] ELISA binding of mouse antibodies to immobilized LILRB-His/FLAG was determined at a fixed concentration of 0.5 ug/mL. As a positive control for target protein immobilization, a titration of anti-FLAG (M2) was performed. FIG. 1 shows ELISA binding data for identified antibodies in the form of a binding heatmap. 0110 indicates an anti-LILRB antibody that binds LILRB1-3, and comprises : (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250; and (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260.

[0180] 0220 indicates an anti-LILRB antibody that binds LILRB1-3, and comprises : (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360.

[0181] 1111 indicates an anti-LILRB antibody that binds LILRB1-3, and comprises : (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150; and (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160.

[0182] 1221 indicates an anti-LILRB antibody that binds LILRB1-3, and comprises : (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450; and (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460.

[0183] 1331 indicates an anti-LILRB antibody that binds LILRB1-3, and comprises : (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530; (d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550; and (f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

Example 2 - Inhibiting HLA-G Tetramer Binding

[0184] Antibodies that inhibit and/or reduce binding of non-classical HLA-G molecules to primary monocytes were then identified. HLA-G*01 :01-PE conjugated tetramer refolded in the presence of human beta 2 microglobulin and peptide RIIPRHLQL. IxlO⁵ CD 14+ monocytes isolated from human peripheral blood are blocked with Fc block (1 :300) for 20 minutes. Test article anti-LILRB antibody (e.g., Antibody 1111) was then added direct to the blocking/unmasking antibody mix to a final concentration of 20 ug (microgram)ZmL (milliliter) and incubated for a further 30 minutes on ice. Finally, HLA- G-PE conjugated tetramer was added to the staining mix at a dilution of 1 : 1500 for 30 minutes. Samples are washed thoroughly and acquired live on a flow cytometer. Three independent assays were performed using monocytes from independent donors, each assay was performed in triplicate.

[0185] Antibodies 0110, 0220, 1111, 1221, and 1331 inhibited HLA-G tetramer binding, showing a decrease in the mean change in HLA-G tetramer binding to monocytes in the presence of a panel of antibodies. A lower MFI is associated with an increase in inhibiting ability.

Example 3 - Inhibiting HLA-A Tetramer Binding

[0186] The ability of antibodies to modulate (e.g., reduce and/or inhibit) binding of classical HLA-A molecules to primary monocytes was also examined. 1x10⁵ CD 14+ monocytes isolated from human peripheral blood are blocked with Fc block (1 :300) and treated with an unmasking antibody (20 ug/mL) for 20 minutes to expose HLA-A binding epitopes on monocyte LILRB proteins. Test anti-LILRB antibody was added directly to the blocking/unmasking antibody mix to a final concentration of 20 ug/mL and incubated for a further 30 minutes on ice. Finally, HLA-A-PE conjugated tetramer (HLA-A*02:01- PE) was added to the staining mix at a dilution of 1 : 100 for 30 minutes. Samples were washed thoroughly and acquired live on a flow cytometer. Three independent assays were performed using monocytes from independent donors, each assay was performed in triplicate. [0187] Antibodies 0110, 0220, 1111, 1221, and 1331 modulated (e.g., reduced and/or inhibited) HLA-A tetramer binding, showing a decrease in the mean change in HLA-A tetramer binding to monocytes in the presence of antibodies.

Example 4 - Binding to LILRB1 and LILRB2 Haplotypes

[0188] The binding affinity of mouse Antibody 1111 was determined by ELISA. ELISA plated were coated with LILRB haplotypes, lug/ml in sodium carbonate buffer (50mM, pH 9.6), lOOpL (microliter) per well and stored overnight 4 Celsius. At the day of ELISA testing, plates were washed 3 times with a wash buffer and blocked with a blocking solution, 200pL per well, for Ihr at room temp with shaking. Three-fold serial dilutions of Antibody 1111 and additional test articles were prepared in the blocking buffer (0- 10,000 ng (nanograms)ZmL), according to ELISA plate layout. After blocking, plate were washed twice with wash buffer and lOOpL standards and samples were added to ELISA plates according to plate layout, and incubated 2hrs at room temp with shaking. Plates were washed three times with wash buffer and goat anti-mouse IgG Fc-HRP detection antibody was applied, diluted to 1 :2000 (by 1 :50 x 1 :40 serial dilution) in blocking buffer at lOOpL/well, and incubated 1 hour at room temperature with shaking. Next plates were washed three times with wash buffer and TMB (3,3',5,5'-tetramethylbenzidine) was added at lOOpL/well, and allow color development for 5 minutes. Reactions were stopped with IN H2SO4, lOOpL/well, and plates were read at 450nm/590nm.

[0189] Antibody 1 1 1 1 bound LILRB2 haplotypes 1 , 2, and 3. Antibody 1 11 1 bound LILRB2 haplotypes 1, 2, 3, and 4. FIGs. 2A-2B show binding curves of Antibody 1111 to LILRB 1 and LILRB2 haplotypes.

Example 5 - Mixed Lymphocyte Reaction (MLR) Assay

[0190JHLA-G binding to LILRB 1 and LILRB2 has been shown to prevent the maturation of dendritic cells (DCs) and is a key mechanism underlying the ability of HLA-G to mediate peripheral tolerance to non-self-antigens. An MLR assay tests the ability of HLA-G to impair DC maturation as assessed by allogenic T cell activation. The ability of antibodies to influence DC maturation in the presence of HLA-G are tested in this assay format.

[0191] Freshly isolated CD14+ monocytes were obtained from PBMCs using bead positive selection and differentiated into dendritic cells in the presence of 50 ng/mL GM- CSF by feeding on days 2 and 4 with a 50% media replacement and cytokine supplementation. On day 5 dendritic cells were matured by the addition of standard maturation cocktail for 2 days. On day 7 mature DCs were washed thoroughly and divided into 96 well u-bottom plates for HLA-G conditioning. HLA-G supernatant (1 :50 dilution) and antibody test articles control antibodies (20 ug/mL) were added for a further 2 days. On day 9 DCs were resuspended, counted and distributed for MLR stimulation into 96 well plates at the appropriate density. PBMCs were then added at a final density of 200k per well in 200pL and appropriate antibody test articles were added to a 20 ug/mL final concentration. Cell supernatants were harvested on day 7 for ELISA analysis of MLR response using IFNy. As positive control anti CD3 (OKT-3) and CD28 (CD28.2) were added to PBMC cultures at 1 ug/mL and 2 ug/mL respectively.

[0192] Firstly, DCs that induce a dose-dependent increase in IFNy (IFN-gamma or IFNg) were identified, the identified DCs are indicative of a Thl immune response when cultured with allogenic PBMCs in a pairwise matrix of DC donors and PBMC responders. Amongst the positive hits the allogenic pair DC #8 and PBMC #2 was identified as suitable donors. FIG. 3A shows the allogenic response (e.g., measured INF-gamma concentrations) induced using DC #8 and PMBC #2. It was hypothesized that HLA-G would reduce allogenic responses however that anti-LILRB blockade could potentially reverse this effect and potentially further polarize Thl . A DC:PBMC ratio of 50: 1 was used to obtain an intermediate level of stimulation (FIG. 3A). Follow up experiments using DC #8 with different PBMC responders demonstrated that the donor exhibits an HLA-G dependent decrease in DC function upon HLA-G conditioning. To assess the impact of antibody test articles (e.g., Antibody 1111) that inhibit HLA-G binding, donor #8 DCs were matured in the presence or absence of HLA-G and MLR was allowed to proceed for 7 days. FIG. 3B shows that HLA-G supernatant impairs DC induction as measured by reduced IFN-gamma production, and importantly, treatment with Antibody 1111 increases IFN-gamma, to the extent that IFN-gamma production was increased beyond the levels observed for DC maturation cocktail (MC) only. (*) indicates Antibody 1111.

Example 6 - Inhibition of HLA-G induced MDSC Suppressive Activity on T cell Proliferation

[0193] A myeloid derived suppressor cell (MDSC) assay was used to determine the influence of antibodies on HLA-G induced MDSC suppressor cell function. HLA-G overexpression supernatant was used to induce MDSCs by co-culture with PBMCs followed by purification of the immunosuppressive CD33+ myeloid population. These MDSC cells are then tested for their ability to suppress autologous T cell proliferation in the presence of mitogenic CD3/28 stimulation in the presence of IL-2.

[0194] MDSCs were induced by co-culturing PBMCs at a density of IxlO⁶ per mL in 10 cm² ultra low binding plates for 7 days in the presence of either supernatant comprising HLA-G5 (from cells overexpressing HLA-G5) (1:50 dilution of 7ug/mL stock by ELISA) or Ni column purified HLA-G5 protein. CD33 positive MDSCs were isolated by bead purification Concurrently, CD3 positive T cells were isolated from a separate aliquot of frozen PBMCs belonging to the same donor and labelled with a lineage tracing label (e.g., a dye). T cells and PBMCs were co-cultured at a 1 : 1 ratio (100k/ well each) in U-bottom 96 well plates in the presence of 10 ng/ mL IL-2 and CD3/28 beads (2.5pL/ 100k T cells). Proliferation was allowed to occur for 3 days at which point cells were harvested and stained for viability using a dye (1 :500) and CD3-PE, CD4-BV421 and CD8-PECy7 (1 : 100 dilution each). Following staining cells were immediately run on the flow cytometer.

[0195] First, the effect of HLA-G on MDSC function was examined. Purified HLA-G5 recombinant protein was titrated into 7-day PBMC cultures using a PBMC donor previously shown to induce MDSC function 500 ng/ mL HLA-G5 (data not shown). Increasing HLA-G5 concentrations led to the acquisition of a T cell suppressive MDSC phenotype in a dose-dependent manner which is abrogated by co-culture of MDSCs with Antibodies that inhibit HLA-G binding. FIG. 4A shows that recombinant HLA-G5 supports the maturation of suppressive MDSC cells, and increasing concentrations of HLA-G5 during PBMC culture generates more potent MDSCs as assessed by T cell proliferation.

[0196] In follow-up experiments HLA-G5 containing supernatant was used to induce MDSC suppressor activity. FIG. 4B shows that Antibody 1111 prevents MDSC differentiation unlike non-HLA-G blocking antibody controls (bars 3 and 4). HLA-G5 induced MDSC function is impaired by HLA-G inhibiting antibody 1111 and restores T cell proliferation. FIG. 4C and FIG. 4E show that Antibody 1111 reverses HLA-G5 generated MDSC suppression on CD4+ T cell proliferation. FIG. 4D and FIG. 4F show that Antibody 1111 reverses HLA-G5 generated MDSC suppression on CD8+ T cell proliferation, m- Antibody 1111 inhibited HLA-G5 induced suppressive MDSCs, increasing T cell proliferation (e.g., as compared to isotype control human IgG2b where HLA-G5 induced suppressive MDSCs and decreased T cell proliferation). HLA-G tetramer also promoted and lead to the acquisition of a T cell suppressive MDSC phenotype.

[0197] For PMBCs co-cultured with HLA-G tetramer, the suppressive phenotype was reverse by Antibody 1111 (but not isotype control human IgG2b). FIG. 4G and FIG. 4H show that HLA-G tetramer-induced MDSCs suppression of CD4+ T cell and CD8+ T cell proliferation was reversed by HLA-G inhibiting antibody 1111 (denoted as 1111).

[0198] Furthermore, treatment with 1111 reverses HLA-G suppression of macrophage polarization (e g., as measured by an increase in TNF-alpha) FIG. 41 shows data demonstrating that mouse and humanized antibody 1111 reduces HLA-G mediated suppression of macrophage polarization.

Example 7 - Humanization of mouse Antibody 1111 (m-Antibody 1111)

[0199] Mouse antibody sequences were humanized through sequence and structural modeling processes. In short, a score was generated based on Protein BLAST is analysis to determine the sequence identity of the mouse Antibody 1111 input sequence databases comprising human antibody sequences. The percent identities of the top matched sequences were averaged to generate the score for the given input sequence.

[0200] For heavy chain (H or HC) humanization, the following framework regions were identified: (i) H-FR-001 : IGHV1-2*O5 IGHJ4*01 : SED ID NO: 171, (ii) H-FR002 : IGHV1-46*O1 IGHJ4*01 : SED ID NO: 172, and (iii) H-FR-003 : IGHV1-46*O1 IGHJ4*01 : SED ID NO: 173 (sequences include CDRs, framework 1 -4 regions can generally be defined by non-CDR sequences). The mouse framework region is provided in SEQ ID NO: 170 (sequence includes CDRs, framework 1-4 regions can generally be defined by non-CDR sequences). Table 1 shows a percent identity matrix of heavy chain framework regions.

Table 1: Heavy Chain Framework Percent Identity Matrix

[0201] For light chain (L or LC) humanization, the following framework regions were identified: (i) L-FR-001 : IGKV1-5*O1 IGKJ2*01 : SED ID NO: 181, (ii) L-FR002 : IGKVl-5*01 IGKJ2*01 : SED ID NO: 182, and (iii) L-FR-003 : IGKVl-33*01 IGKJ2*01 : SED ID NO: 183 (sequence include CDRs, framework 1-4 regions can generally be defined by non-CDR sequences). The mouse framework region is provided in SEQ ID NO: 180 (sequence includes CDRs, framework 1-4 regions can generally be defined by non-CDR sequences). Table 2 shows a percent identity matrix of light chain framework regions.

Table 2: Light Chain Framework Percent Identity Matrix

[0202] Human IgGl constructs comprising L234A/L235 A mutations (attenuating effector function) were generated having the heavy and light chain pairings. The heavy and light chains were the tested in combination. Table 3 shows production yields and endotoxicity of paired heavy and light chains (hlgGl format).

Table 3: Heavy and Light Chain Pairing Properties

[0203] Table 4 shows binding (KD) of paired heavy and light chains (hlgGl format) to LILRB1, LILRB2, and LILRB3. Binding in Table 4 was measure by bio-layer interferometry, however, surface plasmon resonance, isothermal titration calorimetry, or ELISA would be suitable methods for determining binding affinity.

Table 4: Paired Heavy and Light Chain Binding Properties

[0204] Binding and producibility were observed for each of the pairs in combination. The data further supports that heavy chain framework sequences differing in sequence identity by about 24% can be tolerated, inviting that further sequence identity (e.g., about 70%) can be tolerated and identified by the assays described herein. The data also further supports that light chain framework sequences differing in sequence identity by about 17% can be tolerated, inviting that further sequence identity (e.g., about 70%) can be tolerated and identified by the assays described herein.

[0205] The binding of the humanized Antibody 1111 (comprising: (a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 10; (b) a heavy chain complementarity determining region 2 (H- CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 20; (c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 30; (d) a light chain complementarity determining region 1 (L- CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 40; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 50; and (f) a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 60) was then measured by ELISA. ELISAs were performed similar to those described above. FIG. 5A shows binding of humanized Antibody 1111 to LILRB1 and LILRB2. The domains of LILRB2 targeted by Antibody t i l l were determined by ELSIA. In short, plates were coated with lug/ml of full-length Human LILRB2-Fc, D1D2 domain of LILRB2-Fc, or D3Dof LILRB2-hFc in sodium carbonate buffer (50mM, pH 9.6), and ELISA binding was determined as described above. FIG. 5B show ELISA binding of humanized Antibody 1111 to domains 3 and 4 of LILRB2. Interestingly, HLA-G binds domains 1 and 2 of LILRB2, however, as exemplified and described herein, Antibodies 0110 (and 0220, 1111, 1221, and 1331) inhibit HLA-G tetramer binding while binding to domains 3 and 4.

Example 8 - Cell Binding of Antibody 1111

[0206] Antibody 1111 (Antibody 1111), HLA-G dimer, or tetramer binding to T cells, B cells, and NK cells was analyzed using flow cytometry. Whole or LRS-WBC blood specimen(s) were collected from PMBC donor and lymphocytes isolated. For isolation of T cells, CD3+ beads were used for positive selection. For isolation of NK cells, a beadbased kit utilizing the CD56+ marker was used for positive selection. For isolation of B cells, a bead-based kit depleting non-B cells was used.

[0207] 100,000 cells per well were plated. Cells were spun and then the media was removed. 50 pL/well of 1/300 FC blocker and 1/250 L/D aqua was added to all but control cells. To control cells, 50pL/well 1/300 FC blocker was added. Cells were incubated on ice for 20 minutes in dark. Washed once, then resuspend in 50uL/well of titer amounts Antibody 1 11 1 , HLA-G dimer, or HLA-G tetramer. Cells were incubated 1 h on ice in the dark, washed once, and then resuspend in 50uL/well with staining antibodies. Cells were incubated 30 minutes on ice in dark, washed twice with 200pL/well FACS buffer, and resuspended with lOOpL/well FACS buffer. Samples were then analyzed by flow cytometry

[0208] FIG. 6A shows binding of HLA-G dimer and tetramer to T cells isolated from an individual. FIG. 6B shows binding of Antibody 1111 to T cells isolated from an individual. FIG. 6C shows binding of HLA-G dimer and HLA-G tetramer to NK cells isolated from an individual. FIG. 6D shows binding of Antibody 1111 to NK cells isolated from an individual. FIG. 6E shows binding of HLA-G dimer and HLA-G tetramer to B cells isolated from an individual. FIG. 6F shows binding of Antibody 1111 to B cells isolated from an individual. FIG. 6G shows binding of Antibody 1111 to monocytes isolated from an individual. [0209] Collectively, FIGs. 6A-6G demonstrate that pro-immunosuppressive factor HLA- G binds T cells, B cells, and NK cells, and anti-LILRBl-3 antibodies such as Antibody 1111 also binds T cells, B cells, and NK cells. As established above, Antibody 1111 inhibits HLA-G from binding LILRB, thereby reducing the suppression of T cells, B cells, and NK cells, and promoting, e.g., immune activation and/or the maintenance of an activated immune response (e.g., as measured by immune cell proliferation, immune cell polarization, cytokine secretion, etc.).

Example 9 - Antibody 1111 Induced NKL Cell Killing of Cancer Cells

[0210] NK cells express LILRB 1 and not LILRB2. Tumor cells from tumor cell lines were incubated with a composition comprising NK cells and Antibody 1111. Tumor cell survival was measured using flow cytometry. Cell lysis was calculated by the percentage of live/dead-positive tumor cells among total labelled tumor cells. Spontaneous cancer cell death, in the absence of NKL cells, and subtracted from total killing in the presence of NKL cells + 0.1 % polysorbate-20.

[0211] As described above Antibody 1111 binds to NKL cells. FIG. 7A and FIG. 7B show that Antibody 1111 (3 ug/mL) enhances NK cell killing of KMS27 (multiple myeloma cells - FIG. 7A) and PLC/PRF5 (human liver cancer cells - FIG. 7A) tumor cells. A selective LILRB2 antibody had no effect in this assay system (data not shown).

Example 10 - Antibodies 1111 , 1221 , and 1331 Induced PBMC Killing of Cancer Cells

[0212] HLA-G expressing choriocarcinoma JEG-3 cells were treated with in the presence of primary human PBMCs and antibody 1111 that inhibits HLA-G binding. Cell survival was measured at the assay endpoint using FACS to quantify live tumor cells remaining.

[0213] JEG-3 cells were labelled with tracing dye in accordance with manufacturer’s protocol and seeded at a density of 5xlO³ cells/well into 96 well flat-bottom plates and were allowed to adhere for 6 hours at 37 Celsius. Frozen PBMCs were thawed into media, washed, and co-cultured with JEG-3 at the indicated ratios for 6 days. Concurrent with PBMCs HLA-G inhibiting antibody or control was added at the indicated concentrations to a final culture volume of 200uL. Following co-culture, cells were spun down and supernatants discarded. Adherent tumor cells and PBMCs were harvested by enzymatic digestion and counting beads were added. Cells were then stained with dye to discriminate live from dead tumor cells and anti-CD45-PE to identify PBMCs for exclusion gating. Following staining, cells were fixed using 4% PFA for 10 minutes, washed, and run on the flow cytometer. Live tumor cells were determined by gating on the dye positive and Live/Dead negative population, enumerated against the counting beads present within the well.

[0214] PBMCs treated with test article Antibodies 1111, 1221, and 1331 (anti-LILRB antibodies that bind LLRB1-3) showed lower numbers of live tumor cells, in a dose dependent manner. FIG. 8A shows that that Antibodies that inhibit HLA-G binding 1111, 1221, and 1331 facilitates PBMC-mediated killing of JEG-3 cells. FIG. SB shows that Antibody 1111 inhibits JEG-3 cell growth in a dose-response dependent manner.

Example 11 - ELISA Assay of ADA-011 binding with LILRB and LILRA family [0215] The Example demonstrates the concentration dependent binding of ADA-011 to LILRB and LILRA family proteins. The protocol for this experiment is provided below:

1. Coated ELISA 96-well plate (Fisher Scientific #439454) with LILRA and LILRB isoforms (R&D Systems, Table 1) 2pg/ml in sodium carbonate buffer (50mM, pH 9.6), 100 pL per well. Incubated overnight at 4°C.

2. Washed plate 3X with TBST (Thermo Fisher #J77500.K8) and blocked with SuperBlock T20 (Thermo Fisher # 37536), 200 ul per well, for Ih at room temp with shaking.

3. Prepared 3-fold serial dilutions of ADA-011 (ENG DP # 20220301) in SuperBlock T20 (0-10,000 ng/mL), according to ELISA plate layout.

4. Washed plate 2X with TBST and applied 100 pL ADA-011 dilutions to ELISA plate according to plate layout, incubated 2h at room temp with shaking.

5. Washed plate 3X with TBST and applied Goat anti-Human IgG Fc-HRP detection antibody (ThermoFisher # A18817), diluted to 1 :2000 (by 1 :50 x 1 :40 serial dilution) in SuperBlock, 100 pL/well, and incubated Ih at RT with shaking.

6. Washed plate 3X with TBST, applied Super Sensitive Liquid Substrate TMB (Sigma #T4444), 100 pL/well and allowed color development for 4 minutes.

7. Stopped reaction with IN H2SO4, 100 pL/well.

8 Read plate at 450nm on Veriscan.

FIG. 9A provides the data of binding of ADA-011 to LILRB1, LILRB2, LILRB3, LILRB4, and LILRB5. FIG. 9B provides the data of binding of ADA-011 to LILRA1, LILRA2, LILRA4, LILRA5, and LILRA6. Estimated EC50 values estimated from the curves are shown in Table 5 below.

Table 5: Estimated EC50 values:

[0216] The data in Table 5 and FIG. 9A, FIG. 9B, and Table 5 demonstrates that ADA- 011 binds with high affinity to LILRB1, LILRB2, LILRB3, and LILRB5 in the LILRB family. However, as evident from the data, ADA-011 does not bind to LILRB4 in the LILRB family.

[0217] FIG. 10 demonstrates the data for ADA-011 in a dose titration with LILRB family proteins expressed on live cells. CHO cells transfected with individual LILRB genes were incubated with varying concentrations of ADA-011 and mean fluorescence intensity (MFI) were determined by flow cytometry. The experimental protocol for this experiment is provided below.

[0218] CHO cells transfected with individual LILRB genes were seeded at 1x10⁵ /well in a round bottom 96 well plate. The cells were centrifuged at 1500 rpm for 5 min at 4 °C. Then Human TruStain Fcx were added and incubated for 10-15 min on ice. The cells were then washed twice by adding the cell staining buffer and centrifuged at 1500 rpm for 5 min at 4 °C. Various concentrations of ADA-011 antibody were added and incubated for 30 min in the dark on ice. After incubation, the cells were washed twice. Finally, the cells were resuspended in cell staining buffer and acquired using Attune NxT flow cytometer machine.

[0219] Calculated effective concentration of binding is shown in Table 6 below.

Table 6: EC50 data:

Example 12 - Competitive binding assays for ADA-011:

[0220] The example provides data for binding of ADA-011 as compared to commercially available monoclonal antibodies specific to LILRB1, LILRB2, LILRB3, and LILRB4. The protocol for this experiment is provided below.

[0221]Normal viably frozen human PBMCs were thaw and seeded at IxlO⁵ /well in a round bottom 96 well plate. The cells were centrifuged at 1500 rpm for 5 min at 4 °C. Then Live/Dead Fixable Dye were added and incubated for 10-15 min at room temperature. After 10-15 minutes, cells were washed twice by adding with the cell staining buffer and centrifuged at 1500 rpm for 5 min at 4 °C. After the second wash, Human TruStain Fcx were added and incubated for 10-15 min on ice. The cells were then washed twice by adding the cell staining buffer and centrifuged at 1500 rpm for 5 min at 4 °C. Antibody cocktail mix (CD45, CD3, CD4, CD8, CD14, CD16) plus the specific LILRB mono-specific, ADA-011, or isotype control antibodies were added and incubated for 30 min in the dark on ice. After incubation, the cells were washed twice. Finally, the cells were resuspended in cell staining buffer and acquired using Attune NxT flow cytometer machine.

[0222] FIG. 11 provides data for binding of ADA-011 in classical monocytes. Human whole blood was obtained from a commercial vendor, monocytes prepared via negative selection with magnetic beads and levels of target binding were determined by flow cytometry for ADA-011 and different commercially available antibodies previously validated to be mono-specific.

[0223] FIG. 12 provides data for binding of ADA-011 in CD8+ T-cells. Human whole blood was obtained from a commercial vendor, CD8 T cells prepared via negative selection with magnetic beads, and levels of target binding were determined by flow cytometry for ADA-011 and different commercially available antibodies previously validated to be mono-specific.

[0224] FIG. 13 provides data for binding of ADA-011 in NK cells. Human whole blood was obtained from a commercial vendor, NK cells prepared via negative selection with magnetic beads, and levels of target binding were determined by flow cytometry for ADA-011 and different commercially available antibodies previously validated to be mono-specific.

[0225] As evident from the data provided in FIGS. 11, 12, and 13, ADA-011 binds with high affinity to LILRB 1, LILRB2, LILRB3, and LILRB5. Example 13 - Pharmaceutical compositions of ADA-011

[0226] ADA-011 is provided in a solution for infusion. ADA-011 is provided as a sterile solution for infusion at a concentration of 25 mg/mL in a 20 mM L histidine/L histidine monohydrochloride monohydrate buffer with 8% (w/v) sucrose, and 0.015% (w/v) polysorbate 80. This drug product is provided in 10 mL glass vials containing 4 mL sterile solution with a pH of 5.7.

[0227] ADA-011 and pharmaceutical compositions comprising ADA-011 are intended for the treatment of advanced solid tumors.

Example 14 - Development of ADA-011

[0228] This Example provides a sample investigative brochure of ADA-011.

Summary

[0229] ADA-011, a monoclonal antibody product, for the treatment of advanced solid tumors. ADA-011 is in early-stage clinical development with initiation of the first-inhuman study for subjects with advanced solid tumors.

Description

[0230] ADA-011 is a fully humanized immunoglobulin G1 (IgGl) monoclonal antibody with a combination of Leu234Ala and Leu235Ala (LAL A) mutations in the Fc region, which binds to human leukocyte immunoglobulin-like receptors, sub-family B (LILRB) 1, LILRB2, and LILRB3 receptors. For the clinical studies, ADA-011 will be provided as a sterile solution for infusion at a concentration of 25 mg/mL in a 20 mM L-histidine/L-histidine monohydrochloride monohydrate buffer with 8% (w/v) sucrose, and 0.015% (w/v) polysorbate 80. The drug product will be provided in 10 mL glass vials containing 4 mL sterile solution with a pH of 5.7. The molecular weight of ADA-011 is 145 kDa.

Target Indication and Usage

[0231] ADA 011 is intended for the treatment of advanced solid tumors.

Summary of Non-clinical Information:

[0232] A comprehensive nonclinical pharmacology, pharmacokinetic (PK), and toxicology program was conducted to support the clinical program for ADA-011.

[0233] Primary pharmacodynamic studies confirmed that ADA-011 binds to LILRs on human immune cells and elicits an immune-mediated antitumor effect in murine cancer models. [0234] Safety pharmacology studies in Cynomolgus monkeys as a part of the 4-week, repeat-dose. Good Laboratory Practice (GLP) toxicology study determined ADA-011 has no adverse effects on the central nervous system (CNS) or cardiovascular (CV) parameters.

[0235] Single dose administration in mice did not show dose-proportional changes for maximum observed concentration (Cmax) but was dose-proportional with regard to area under the concentration time curve (AUC) at the last measurable timepoint (AUCiast). Average half-life (T1/2) ranged from 192 hours to 316 hours across the tested dose range. [0236] Single dose administration in Cynomolgus monkeys at low doses resulted in rapid clearance and is likely due to target-mediated drug disposition (TMDD). Average Cmax and AUC from 0 to 48 hours (AUCo-48 ) was not dose-proportional across tested doses. No accumulation was observed following administration of a second dose at any level.

[0237] Repeated weekly dosing in Cynomolgus monkeys in the GLP toxicology study resulted in dose-proportional increases in Cmax and AUC from 0 to 168 hours (AUCO-1681I) on Day 1 and more than dose-proportional increases in exposure at higher doses on Day 22; this non-linear trend is likely due to the development of anti- ADA-011 antibodies.

[0238] ADA-011 declined in a biphasic manner for both studies in Cynomolgus monkeys with a mean T1/2 of less than 60 hours across all doses. Overall, no significant increase in systemic exposure was observed after repeat doses of ADA-011, and no gender differences were observed in either of the completed studies in Cynomolgus monkeys.

[0239] ln the 10-day, repeat-dose, non-GLP toxicology study, there were no ADA-01 1 - related adverse effects on clinical signs, food consumption, body weight, clinical pathology, or macroscopic and microscopic findings for any tested dose levels. All Cynomolgus monkeys survived in the 4-week, repeat-dose, GLP toxicology study. There were no ADA-011 -related effects on body weights, qualitative food consumption, hematology, coagulation, clinical chemistry, urinalysis, cytokines, organ weights, or macroscopic findings. One female in the 10 mg/kg dose group had severe vomiting and decreased activity at one timepoint. No abnormalities in heart rhythm were observed. Dose-independent decreases in absolute CD159a+ natural killer (NK) cells were observed. Microscopic findings consistent with drug immunogenicity at the 30 and 100 mg/kg doses were observed.

[0240] Local tolerance assessments determined that ADA-011 injections did not produce any test article-related irritation at injection sites. Additional toxi cities using human peripheral blood mononuclear cells (PBMCs) determined ADA-011 does not induce dose- dependent cytokine response. ADA-011 also does not induce antibody-dependent cell- mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or compliment-dependent cytotoxicity (CDC).

[0241] ADA-011 has not been previously tested in a clinical setting.

Background

[0242] Increasing knowledge on the role of the immune system in the development and progression of cancer has led to the development of various immunotherapy regimens, such as immune-checkpoint inhibitors (ICIs), cancer vaccines, and cellular therapies. While successful immunotherapies can generate long-term remission, not all patients and tumor types respond to treatment. Some patients relapse after an initial response, and some therapies are associated with significant toxicity. Anti-PD-1 and anti-PD-Ll ICIs, including the Food and Drug Administration (FDA)-approved agents pembrolizumab and nivolumab, are on the forefront of immunotherapy for cancer patients treating a variety of malignancies including melanoma, non-small-cell lung carcinoma, and head and neck squamous cell carcinoma. Studies combining anti-PD-l/PD-Ll agents with other immunotherapy regimens have shown promising results, and an acceptable balance between efficacy and toxicity is key in the development of new immunotherapies. Swaika A, Hammond WA, Joseph RW, Current state of anti-PD-Ll and anti-PD-1 agents in cancer therapy. Mol Immunol, 2015. 67(2 Pt A): p. 4-17.

[0243] Receptors LILRB1-LILRB5 have recently gained attention as promising targets for cancer treatment. The human LILRB genes are a group of type I transmembrane glycoproteins encoded in a region called the leukocyte receptor complex. Martin AM, Kulski JK, Witt C, Pontarotti P, Christiansen FT, Leukocyte Ig-like receptor complex (LRC) in mice and men. Trends Immunol, 2002. 23(2): p. 81-88. The LILRBs contain extracellular Ig-like domains, capable of binding multiple ligands, and intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that upon ligation can send an inhibitory signal. FIG. 14 provides a schematic of LILRBs and their proposed ligands. LILRBs are predominantly expressed by cells of the hematopoietic system with the majority of the LILRBs being expressed on myeloid cells, such as mast cell progenitors, monocytes, macrophages, and dendritic cells (DCs). Kang X, Kim J, Deng M, John S, Chen H, Wu G, et al., Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors. Cell Cycle, 2016. 15(1): p. 25-40; Burshtyn DN,Morcos C, The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors. J Immunol, 2016. 196(3): p. 947-955; van der Touw W, Chen HM, Pan PY, Chen SH, LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol Immunother, 2017. 66(8): p. 1079-1087; Zhao J, Zhong S, Niu X, Jiang J, Zhang R,Li Q, The MHC class I-LILRB1 signalling axis as a promising target in cancer therapy. Scand J Immunol, 2019. 90(5): p. el2804; Zhang J, Mai S, Chen HM, Kang K, Li XC, Chen SH, et al., Leukocyte immunoglobulin-like receptors in human diseases: an overview of their distribution, function, and potential application for immunotherapies. J Leukoc Biol, 2017. 102(2): p. 351-360. The activation of LILRBs on immune cells by their ligands may contribute to immune evasion by a variety of malignant and infectious diseases such as melanoma, lung cancer, and renal cancer. LILRBs transduce signals via their ITIM motifs that lead to negative regulation of immune cells activation. Because the immunosuppressive capabilities of LILRBs are similar to those of the immune checkpoint proteins such as CTLA4 and PD-1, LILRBs are considered to be immune checkpoint factors and are expected to play a significant role in human immunity and cancer development.

Rationale for the development of ADA-011

[0244] Antibody therapeutics targeting members of the LILRB receptor family are being explored as a new class of checkpoint inhibitor therapy in various malignancies as single agents and in combination with anti-PD-(L)! therapy. Siu LL, Wang D, Hilton J, Geva R, Rasco D, Perets R, et al., First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid- Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Clin Cancer Res, 2022. 28(1 ): p. 57-70. ADA-011 is a fully humanized IgGl monoclonal antibody, with an LALA mutation in the Fc region, which binds to the three human LILRB 1, LILRB2, and LILRB3 receptors and inhibits ligand mediated immunosuppression that occurs upon activation of the LILRB receptors. This key pathway represents a novel approach in immuno-oncology with the potential to benefit patients with cancer in the future.

[0245] The focus of the ADA-011 clinical studies will include patients with advanced solid tumors, including patients whose tumors are more likely to have a high number of LILRB 1/2/3 positive tumor infiltrating lymphocytes. Tumor types that potentially fall into this category include melanoma, lung cancer, renal cancer, ovarian cancer, esophageal cancer, liver cancer, and gastric cancer. Modulating the inhibitory signals transmitted via ligand binding to LILRB 1, LILRB2, and LILRB3 offers a new therapeutic opportunity to help expand the treatment options for cancer patients diagnosed with a variety of different malignancies. Physical, Chemical, and Pharmaceutical Properties and Formulations of ADA-011 Overview

[0246] The structure of ADA-011 is provided in FIG. 15. The monoclonal antibody is an IgGl subclass antibody, which is composed of two heavy chains of the IgGl (yl) subclass and two light chains of the Kappa (K) subclass. The four chains are stabilized by multiple disulfide bonds. ADA-011 is a glycoprotein and the constant region of each heavy chain contains a single N-linked glycan site at residue Asparagine (N) 299. The leucine amino acids at positions 236 and 237 on the heavy chain have been mutated to Alanine (L236A / L237A) in order to silence effector function of IgGl antibody. Finally, the C- terminal- Lysine of the heavy chain was deleted to eliminate heterogeneity generated by the proteolytic clipping of this residue. The theoretical deglycosylated molecular weight of ADA-011 is 145331.6934 Da.

General Description of Manufacturing Process

[0247] The cell culture manufacturing process includes thawing of a master cell bank vial, cell expansion in shake flasks and bioreactors, cell culture in the 2000 L production bioreactor with a working volume of 1000 L, and harvest. The unprocessed bulk is tested for bioburden, mycoplasma, adventitious viruses in vitro, retroviruses, and speciesspecific viruses. The purification manufacturing process includes several chromatography and filtration steps in accordance with good manufacturing practice (GMP) regulations. After viral filtration (0.2 pm filter), ultrafiltration and diafiltration (0.2 pm filter), the sterile product is diluted to the target concentration of 25.0 (22.5- 27.5) mg/mL using Excipient 1 Stock Solution (20 mM Histidine buffer, 40% (w/w) sucrose, pH 5.7) and Excipient 2 Stock Solution (20 mM Histidine buffer, 5% (w/w) PS80, pH 5.7) to reach a final concentration of 8% (w/v) sucrose and 0.015% (w/v) polysorbate 80 (PS80) respectively. The final drug substance is stored at 4 ± 10 °C with an extractable volume of 4 mL/vial. The filled drug product vials are bulk packaged and stored at 2 - 8°C.

Quality Control

[0248] The ADA-011 drug product is manufactured in compliance with GMP regulations, and no excipients of human or animal origin have been used. Bioburden and endotoxin sampling is performed at each process step during the purification process. The formulated ADA-011 drug substance is 0.2 pm sterile filtered before formulation and release testing is carried out to ensure drug substance quantity, potency, purity, and absence of microbial contaminations. [0249] The drug product GMP manufacturing area includes separate areas for component and equipment preparation, formulation, filling, inspection, and bulk packaging of the drug product. Sterile filtration, filling, stoppering, and capping all occur under a Grade A environment. A filling pump with an automatic filler and stoppering unit are enclosed within an Open Restricted Access Barrier System (ORABS) to fully enclose the aseptic process and provide a Grade A environment. Capping is also performed under a Grade A environment. A manual 100% visual inspection is performed on the filled vials by production personnel, followed by a statistically based acceptance quality limit inspection by Quality Assurance. Release and stability samples are taken after visual inspection.

Active Product Composition:

[0250] Table 7 provides the composition of an exemplary ADA-011 drug product formulation.

Table 7: Composition of ADA-011 Sterile Solution for Infusion

BP = British Pharmacopoeia; ChP = Chinese Pharmacopoeia; EP = European Pharmacopoeia; JP = Japanese Pharmacopoeia; NF = National Formulary; q.s. = sufficient quantity; USP = United States Pharmacopeia.

Stability of the ADA-011 Product

[0251] Formal stability studies are in progress for the lot of ADA-011 drug product designated for this study, in accordance with ICH Q5C guidelines. Stability assessment of ADA-011 drug product includes the following conditions: 1 month of long-term stability data (5 ± 3 °C), 1 month of accelerated stability data (25 ± 2 °C), and 1 month of stress stability data (40 ± 2 °C).

[0252] Stability studies on the clinical batch will continue throughout the duration of use of the drug product made from this active pharmaceutical ingredient in planned clinical studies, and results will be submitted to the investigational new drug (IND) application on a regular basis as they become available. New batches will also be monitored on stability.

Storage and Handling:

[0253] The ADA-011 drug product is supplied in 10 mL Type I clear borosilicate glass vials with flip-off seals over 20 mm grey rubber stoppers. The drug product should be stored at 2 to 8°C until administration.

Nonclinical Information:

[0254] A comprehensive nonclinical program including pharmacology, PK, and toxicology studies has been conducted to support the clinical investigation of ADA-011 in subjects with advanced solid tumors.

[0255] In vitro, ex vivo, and in vivo primary pharmacodynamic studies were performed (LILR binding assays, immune cell-based functional assays, and assessment of antitumor activity) with ADA-011. Safety pharmacology evaluations, including CNS and CV system assessments, were included in a GLP-compliant 4-week repeat-dose toxicity study in Cynomolgus monkeys with weekly IV administration of ADA-011.

[0256] The PK characteristics of ADA-011 were investigated as a part of both nonclinical PK and TK studies in mice and Cynomolgus monkeys, respectively. Overall, no significant increase in systemic exposure was observed after repeat doses of ADA-011. No gender differences in TK parameters were observed in studies that utilized Cynomolgus monkeys. The bioanalytical methods used for the detection of ADA-01 1 were developed and validated in mice and Cynomolgus monkeys and are summarized below.

[0257] The in vivo safety profile of ADA-011 (administered by IV injection) was evaluated in a 10-day dose-range finding study and 4-week, repeat-dose, GLP study in Cynomolgus monkeys. Additional in vitro tests to assess the ability of ADA-011 to elicit multiple immune-mediated mechanisms were evaluated using appropriate human cell culture systems.

Primary Pharmacodynamics

[0258] A summary of the primary pharmacodynamics studies is provided in Table 8 below. Table 8: Summary of Primary Pharmacodynamics Studies

Clq = compliment component Iq; CCL = chemokine (C-C motif) ligand; DCs = dendritic cells; ELISA = enzyme-linked immunosorbent assay; FACS = fluorescence activated cell sorting; HLA = human leukocyte antigen; IFN-y = interferon-gamma; IL = interleukin; IP = intraperitoneal; LILR = leukocyte immunoglobulin-like receptor; LPS = lipopolysaccharide; MDSCs = myeloid-derived suppressor cells; NHP = non-human primate; NK = natural killer; NKT = natural killer T; PBMCs = peripheral blood mononuclear cells; SCID = severe combined immunodeficiency; SPR = surface plasmon resonance; TNF-a = tumor necrosis factor alpha.

In vitro primary pharmacodynamic studies

Binding Affinity and Profile of Humanized ADA Oil to the Human LILR Family

[0259] The mouse hybridoma 9C9.E6 was humanized and sequence optimized. Study No. ADA-PH-004. The humanized antibody is termed ADA-011. The binding of ADA-011 to different LILR family members was evaluated and Table 9 shows the dissociation constants (Ka) for binding of ADA-011 to the specific LILR proteins. ADA-011 was found to bind to LILRB1, B2, and B3 with low nM affinity with binding to LILRA1 and LILRA3 being approximately 3-fold weaker.

Table 9. Binding of ADA-011 to Select Members of the Human LILR Family of

Receptors

[0260] Cell microarray technology was used to screen for specific off-target binding interactions of ADA-011 (Study No. RP1438/RP1658). Human embryonic kidney cells were treated with 5 mg/mL of ADA-011 and fixed to screen for binding of 5868 full-length human plasma membrane proteins and cell surface-tethered human secreted proteins plus a further 371 human heterodimers. This revealed 25 library hits altogether. [0261 ] Each library hit was re-expressed, along with 2 control receptors, and re-tested with 5 mg/mL of ADA-011 or control treatments. This was performed on both fixed and live cells. After removing hits that were not reproduced between the library and confirmation/specificity screen, were non-specific, due to the binding of control molecules, or were non-significant (very weak intensity), 9 interactions remained that were specific to ADA-011.

[0262] Of those 9 specific interactions, ADA-011 showed specific interactions with its primary targets, LILRA1, LILRB1 (2 isoforms, 1 and 5), and LILRB2 on both fixed and live cell microarrays. Additional interactions were observed with other leukocyte immunoglobulin-like receptor family proteins, LILRA3 (both secreted and tethered-secreted forms), LILRA6, LILRB3, and LILRB5 on both fixed and live cell microarrays. These results indicate that ADA-011 binds to its primary targets LILRA1, LILRB1, LILRB2, LILRA3, LILRA6, LILRB3, and LILRB5.

Binding Affinit and Sequence Homology in Different Species

[0263] In order to enable the selection of a relevant species for toxicology studies prior to the commencement of clinical trials in patients, the cross-reactivity of ADA-011 was investigated in vitro against other non-human sequences (Study Nos. ADA-PH-008, ADA-PH-010, and ADA-PH-011). The LILR family of genes is considered primate specific. The paired immunoglobulin-like receptor is considered a mouse relative of the human LILRs but is not considered a LILR homolog. A bioinformatic analysis of all public DNA sequence databases was conducted by Monoceros Biosystems to determine the Cynomolgus monkey (crab eating macaque) LILR sequences and compare such sequences to the human LILR gene family. In summary, 10 LILRA genes were identified in the Cynomolgus monkey with two versions of LILRA2, and LILRA6, three versions of A3, and one version of the other LILRA sequences. In Cynomolgus monkey, five LILRB genes were identified with two versions of LILRB1 and no apparent LILRB2 sequence. The human LILRB2 gene sequence was found to cluster tightly with nonhuman primate (NHP) LILRB 1 orthologs, LILRB la and LILRB lb, and no NHP ortholog of LIRLB2 was identified

[0264] The percent identity between certain human LILR genes (LILRA1, A3, and LILRB 1, B2, and B3) and the closest Cynomolgus monkey LILR proteins is shown in FIG. 16. This comparison shows that there is reasonable identity across the extracellular domain between these human and NHP LILR proteins.

[0265] ADA-011 was found to bind to recombinant proteins generated from the extracellular domain of human and Cynomolgus monkey LILR proteins by enzyme-linked immunosorbent assay (ELISA) with ICso values in the 0.07 to 0.43 nM range Table 10. ADA-011 has similar binding affinities to human and NHP LILRB1, LILRA1 and LILRA3. The affinity of ADA-011 binding to NHP LILR sequences is similar to the affinity of ADA-011 to human LILR sequences with the affinity constant difference between human LILRs and NHP LILRs being less than 10-fold. When taken together, these data show that ADA-011 binds to NHP sequences with affinities that are similar, and in some cases stronger, than to the human LILR sequences. The data suggests that the Cynomolgus monkey is a pharmacologically relevant species for primary pharmacodynamic and toxicology studies specifically for antibodies that bind to LILRB 1, LILRA1, and LILRA3.

Table 10 .Binding of ADA-011 to Recombinant Proteins Generated from the cDNA Sequence of Human LILRs and Cynomolgus Monkey LILRs as Measured by ELISA

[0266] ADA-011 binding to human and Cynomolgus monkey PBMCs are shown in FIG.

17A and FIG. 17B respectively. Binding of ADA-011 to Fc Receptors and Clq

[0267] The Fey receptors are known to play a role in the effector function observed for a large number of therapeutic antibodies. FcyRl, for example, is known to be responsible for the antibody-dependent cell-mediated cytotoxicity (ADCC) and complimentdependent cytotoxicity (CDC) functions observed with IgGl antibodies. ADA-011 contains a LAL A mutation and was thus designed to minimize binding to the Fey receptors, specifically FcyRl. Binding of ADA-011 to the different Fey receptors was evaluated in Study No. CBLX070821-1 A-SPR and the estimated Ka values are tabulated in Table 11. ADA-011 had low affinity for the human Fey receptors, whereas an Fc competent human IgGl isotype control was observed to have nM affinity against FcyRl. These data suggest that ADA-011 would have minimal ability to trigger the effector functions normally associated with the binding of IgGl antibodies to FcyRl.

Table 11. Binding of ADA-011 to the Different Human Fey Receptors

[0268] Binding of human therapeutic antibodies to the complement component Iq (Clq) can trigger the initiation of the complement system. Binding of Clq to the Fc region of such therapeutic antibodies is a key interaction responsible for complement binding. LAL A mutations are known to reduce Clq binding and as such reduce the potential of the antibody to trigger complement activation. In Study No. CBLX092421-2A-SPR, ADA-011 was thus evaluated for its ability to bind to Clq and no binding was observed. An IgGl isotype control with a functional Fc region was found to bind to Clq with 87 nM affinity. This data suggests that ADA-011 would not be able to trigger the initiation of complement activation.

Expression of LILR Proteins Across Multiple Human Immune Cell Types

[0269] The expression of LILRB1, B2, B3, and B4 was evaluated across multiple immune cell types within different PBMC donors (Study No. ADA-PH-014). All four LILRB proteins are expressed within the myeloid cell population. LILRB 1 is also expressed in B cells, natural killer (NK) and natural killer T (NKT) cells, and to a minor extent in CD8⁺ T cells.

[0270] The expression of LILRB1, LILRB2, LILRB3, and LILRB4 was also evaluated in different cell populations used in the cell based functional assays (monocytes, dendritic cells [DCs], and human leukocyte antigen [HLA]-G induced myeloid-derived suppressor cells [MDSCs]) (Study Nos. ADA-PH-015A, ADA-PH-015B, and ADA-PH-015C, respectively). LILRB 1 and LILRB 3 were the predominant LILRBs expressed in monocytes, LILRB4 was the LILRB predominantly expressed in DCs, and LILRB1, LILRB3, and LILRB4 being the LILRBs expressed in HLA-G induced MDSCs.

[0271] Multiple experiments across different PBMC donors included an analysis of the expression of the LILRA family members in addition to LILRB family members. The most commonly expressed LILRA family member was LILRA1, which was expressed in monocytes and the derived dendritic cell populations, B cells and to a minor extent T cells. LILRA6 was also found to be expressed in the myeloid cell population (FIG. 18). The data generated across multiple immune cell types from different PBMC donors is consistent with that described in the literature.

Bindin of ADA-011 Across Multiple Human Immune Cell Types

[0272] The ability of ADA-011 to bind to different immune cells was also evaluated. In Study No. ADA-PH-016, ADA-011 was observed to bind to monocytes (FIG. 19). Similarly, ADA-01 1 binding was demonstrated in NK cells, B cells, and T cells (FIG. 20) isolated from human PBMC donors (Study Nos. ADA-PH-017A, ADA-PH-017B, and ADA-PH-017C). The data show that ADA-011 is capable of binding to the different immune cells that express LILRBs.

Effect of ADA-011 on Macrophage Polarization

[0273] To determine the effect of ADA-011 on macrophage polarization, two distinct assays were performed using monocytes isolated from multiple PBMC donors and stimulated with macrophage colony-stimulating factor (M-CSF) to generate macrophages.

[0274] The first experiment evaluated the effect of ADA-011 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-a production (Study No. ADA-PH-018). Results showed that ADA-011, relative to an appropriate isotype control, was found to enhance LPS-induced TNF-a production in monocyte-derived macrophages (FIG. 21). The data demonstrates that ADA-011 enhances LPS induced production of TNF- a in Monocytes Differentiated into Macrophages from Multiple PBMC Donors.

[0275] The second experiment evaluated the effect of ADA-011 on HLA-G suppression of TNF-a production (Study No. ADA-PH-019). Results showed that both ADA-011 and 9C9.E6 (the mouse hybridoma version of ADA-011), relative to appropriate isotype controls, reversed HLA-G suppression of LPS-induced TNF-a production in monocyte- derived macrophages (FIG. 22). The data in FIG. 22 demonstrates that ADA-011 treatment enhances LPS induced TNF-a production and reverses HLA-G Suppression of LPS induced TNF- a production.

Effect of ADA-011 on Myeloid-Derived Suppressor Cell Function

[0276] To determine the effect of ADA-011 on MDSC functioning, an in vitro stimulation assay was performed using MDSCs and T cells isolated from multiple PBMC donors (Study No. ADA-PH-020). In the absence of ADA-011, HLA-G-treated MDSCs suppressed expansion of cytotoxic CD8⁺ T cells. Treatment with ADA-011 in culture resulted in an increase in the number of proliferating cytotoxic CD8⁺ T cells (FIG. 23). This indicates ADA-011 treatment reverses the immunosuppressive effects of MDSCs on cytotoxic T cell proliferation. The data in FIG. 23 demonstrates that ADA-011 treatment reverses HLA-G treated MDSC Suppression of CD3/CD28 stimulation of CD8+ T cell proliferation.

Effect of ADA-011 on Mixed Lymphocyte Reactivity

[0277] To determine the effect of ADA-01 1 on mixed lymphocyte reactivity, PBMCs from Donor 1 were incubated with PBMCs from Donor 2 and the levels of secreted interferon (IFN)y were measured (Study No. ADA-PH-021). HLA-G can markedly suppress the levels of IFNg detected in this mixed lymphocyte reaction assay, and results showed that ADA-011 can reverse the HLA-G mediated suppression of IFNy production (FIG. 24). The data in FIG. 24 demonstrates that ADA-011 treatment reverses HLA-G suppression of IFNy production in a mixed lymphocyte reaction.

[0278] Together, the results from the macrophage polarization assays, MDSC assays, and mixed lymphocyte reactions assays demonstrated that ADA-011 promotes inflammatory activation in cells of myeloid origin.

ADA-011 Enhanced NK Cell Killing,

[0279] The NKL cell line was chosen as an appropriate NK cell line for assessing the ability of ADA-011 to enhance NK cell cytotoxicity. Robertson MJ, Cochran KJ, Cameron C, Le JM, Tantravahi R,Ritz J, Characterization of a cell line. NKL, derived from an aggressive human natural killer cell leukemia. Exp Hematol, 1996. 24(3): p. 406- 415. Chen et al. (Chen H, Chen Y, Deng M, John S, Gui X, Kansagra A, et al., Antagonistic anti-LILRBl monoclonal antibody regulates antitumor functions of natural killer cells. J Immunother Cancer, 2020. 8(2)) showed that NKL cells express LILRB1 and have the potential to enhance NK cell killing when incubated with an antibody capable of binding to LILRB1. FIG. 25 Error! Reference source not found. shows that NKL cells express LILRB1, and that ADA-011 is capable of binding to NKL cells (Study No. ADA-PH-026). In FIG. 25, the left hand panel shows the degree of LILRB1 expression on the NKL cell line as measured by flow cytometry. Right hand panel shows the binding of ADA-011 to NKL cells.

[0280] The ability of ADA-011 to enhance NKL cell killing of two specific cancer cells lines, the PLC/PRF/5 liver cancer cell line and the KMS27 my eloma cell line, was then evaluated (Study No. ADA-PH-027). These two cell lines were chosen as they expressed HLA-A, B, and C and b2 microglobulin, and that a Fc-LILRBl construct was found to bind efficiently to both cell lines. ADA-011 enhanced both NKL cell killing of both PLC/PRF/5 and KMS27 cells with the degree of cytotoxicity being greatest for the KMS27 cell line (FIG. 26). The data in FIG. 26 demonstrates that ADA-011 enhances the NK cell mediated killing of PLC/PRF/5 Liver Cancer Cells (Left Panel) and KMS27 Myeloma Cells (Right Panel).

ADA-011 Effects on C tokine-Release in Primary Human PBMCs Ex Vivo

[0281] The interaction of immune cells with their specific target (tumor) cells is known to induce cytokine and chemokine secretion which may in part drive the cell killing activity of such immune cells. Two of the most common cytokines produced by NK cells are TNF-a and IFNy, although other cytokines and chemokines, such as interleukin (TL)- 5, IL- 10, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MlP)-la, MIP-lb (chemokine [c-c motif] ligand [CCL]4), IL-8, and RANTES (CCL5), have also been reported to be secreted by NK cells either in response to exogenous cytokines or after engagement with target cells. Fehniger TA, Shah MH, Turner MJ, VanDeusen JB, Whitman SP, Cooper MA, et al., Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol, 1999. 162(8): p. 4511-4520; Fauriat C, Long EO, Ljunggren HG,Bryceson YT, Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood, 2010. 115(11): p. 2167-2176.

[0282] The objective of Study No. ADT02 was to evaluate the potential of ADA-011 to trigger cytokine release in primary human PBMCs derived from ten healthy human donors. The response of PBMC samples to treatment with various doses of ADA-011 was compared to Anti-CD3 antibody (OKT3 clone) treatment (positive control), human IgGl isotype control antibody (negative control), as well as a no treatment control. PBMC samples were treated in soluble and wet-coated (plate-bound) treatment formats.

[0283] In vitro cytokine release by PBMCs was evaluated 24 hours after treatment. The levels of IL-2, IL-6, TNF-a, IFNy, and CCL4 in tissue culture supernatants were measured using a cytometric bead array approach. Anti-CD3 stimulation, under both formats, resulted in a response from all donors with all cytokines tested, demonstrating that these donors had the capacity to release cytokines in response to a stimulus. No IL-2, TNF-a, or IFNy was detected for any donors in the absence of treatment. IL-6 and CCL4 were not released in the absence of treatment for most donors, except for Donor 7, which had elevated levels at baseline. Results showed that ADA-011 did not induce a dose-dependent cytokine response for any of the cytokines tested under either format.

In Vivo Primary Pharmacodynamic Studies

Antitumor Activity of 9C9.E6 in a Tumor Cell PBMC Admixed Model

[0284] The ability of 9C9.E6 (the mouse hybridoma version of ADA-011) to generate an antitumor response in vivo was evaluated in a tumor cell PBMC admixed model (Study No. ADA-PH-023). JEG-3 choriocarcinoma cells were used as the tumor cells in these experiments as they are known to express HLA-G. In these experiments JEG-3 tumor cells were mixed with a PBMC donor cells and implanted into BALB/c severe combined immunodeficiency (SCID) mice. Tumor growth was monitored over time in both a control vehicle arm and in mice who were treated with 20 mg/kg 9C9.E6 three times per week for 3 weeks. 9C9.E6 (blue line) showed significant (** = p < 0.05, *** = p < 0.01) antitumor activity in this model system (FIG. 27). The data in FIG. 27 demonstrates in vivo antitumor activity of 9C9.E6 (ADA 011 parental antibody shown in blue) in a JEG- 3/PBMC Admixed Mouse Model

[0285] The degree of antitumor activity observed in the JEG-3/PBMC admixed model is most likely an underestimate given the fact that tumors in the vehicle control animals grew very rapidly and a number of mice had to be euthanized as per Institutional Animal Care and Use Committee protocol when the tumors size grew beyond 1000 mm³. Table 12 shows the number of mice remaining alive in both arms of each experiment at the key times when tumors were being measured.

Table 12. Number of Surviving Animals at Time of Tumor Measurement in the JEG-

3/PBMC Tumor Admixed Mouse Model

ANOVA — Analysis of variance

ADA-011 Enhanced NK Cell Mediated Antitumor Activity in a PLC/PRF/5 Tumor Model

[0286] The ability of ADA-01 1 to enhance NK cell-mediated killing in vivo was evaluated using a PLC/PRF/5 liver tumor model (Study No. ADA-PH-028). PLC/PRF/5 liver cancer cells were into BALB/c SCID mice. Tumor growth was monitored over time in both a control vehicle arm that either received (red line) or did not receive (black line) and infusion of NKL cells and in mice who were treated with 20 mg/kg ADA-01 1 3 times per week for 4 weeks that received an infusion of NKL cells (blue line). Treatment with ADA-011 showed significant antitumor activity in this model system in combination with NKL infusion (FIG. 28). NKL infusion alone had minimal effect on tumor volume compared with untreated control tumors. FIG. 28 demonstrates that ADA Oi l Enhances the NK Cell Mediated Killing of PLC/PRF/5 Liver Cancer Cells In Vivo.

Safety Pharmacology

[0287] Safety pharmacology assessments of the cardiovascular system (heart rate, and electrocardiograms [ECG]) and CNS were performed as part of the GLP-compliant 4 week repeat-dose toxicity study in Cynomolgus monkeys with weekly IV administration of ADA-01 1 at dose levels of 0, 10, 30, and 100 mg/kg/dose (Study No. 20330080). Results showed no CNS-related adverse clinical signs, during the study. Furthermore, there were no treatment-related changes in ECG intervals, including QTc, at any dose level.

Nonclinical Pharmacokinetic Information

[0288] The PK characteristics of ADA-01 1 were investigated as a part of both nonclinical PK (mouse) and TK studies in Cynomolgus monkeys. A total of 3 studies were performed: 1) a single-dose non-GLP pharmacology study in BALB/c SCID mice that evaluated doses in the 3 to 30 mg/kg range, 2) a dose range-finding non-GLP study in Cynomolgus monkeys that evaluated doses in the 1 to 100 mg/kg range, and 3) a repeat dose GLP toxicology study in Cynomolgus monkeys that examined a single dose of 10 mg/kg and weekly doses of ADA-011 ranging from 10 to 100 mg/kg.

[0289] The immunoassay bioanalytical methods used for the detection of ADA Oi l in BALB/c SCID mice blood (enzyme-linked immunosorbent assay [ELISA]) and Cynomolgus monkey serum (electrochemiluminescence immunoassay [ECL]) were developed and validated. An overview of the studies conducted in the aDA-011 nonclinical PK/TK program is shown in Table 13 below.

Table 13. List of Completed Pharmacokinetic/Toxicokinetic Studies for ADA-011

GLP = Good Laboratory Practice; IP = intraperitoneal; IV = intravenous.

Methods of Analysis

[0290] ADA-011 is a monoclonal antibody (mAb) and was analyzed via immunoassay in the PK study in BALB/c SCID mice, and in the TK dose range-finding and GLP studies in Cynomolgus monkeys. A list of bioanalytical methods is provided in Table 14 below.

Table 14. Summary of Bioanalytical Methods

ECL = electrochemiluminescence immunoassay; ELISA = enzyme-linked immunosorbent assay; GLP = Good Laboratory Practice; LLOQ = lower limit of quantification.

Note: The assay utilized to measure ADA-011 in Cynomolgus monkeys was qualified for study DRF001 and later validated for the GLP study (20330080).

Ah sorption

Pharmacokinetics of ADA 011 After Single Dose Administration in Female BALB/c

Mice

[0291] Pharmacokinetic parameters of ADA-011 were evaluated in a non-GLP, singledose study in 8- to 10-week-old female BALB/c SCID mice (Study TRx_615-l). ADA- Oi l was administered by intraperitoneal (IP) injection at dose levels of 3, 10, and 30 mg/kg (16 mice/dosing group). Blood samples were obtained at 1-, 3-, 6-, 24-, 48-, 72-, 96-, 168-, 336-, 504-, and 672-hours post-dose.

[0292] The average Cmax of ADA-011 following single IP injection was 38.3, 107, and 492 pg/mL at doses of 3, 10, and 30 mg/kg, respectively. Average area under the curve from time 0 to the infinity (AUCinf) was calculated to be 10295, 37875, and 111625 hr*pg/mL at doses of 3, 10, and 30 mg/kg, respectively. Average resulted half life (Tl/2) was estimated to be 192 hours (8.0 days), 210 hours (8.75 days), and 316 hours (13.17 days) at doses of 3, 10, and 30 mg/kg, respectively.

[0293] Average Cmax increased in a less than dose proportional manner between doses of 3 and 10 mg/kg and in a more than dose proportional manner between doses of 3 to 30 mg/kg and 10 to 30 mg/kg. Average AUCinf was nearly dose proportional across the three tested dose levels.

Toxicokinetics of ADA-011 After Administration in Cynomolgus Monkeys Across a Dose Range

[0294] Toxicokinetic parameters of ADA 011 were evaluated in a non-GLP dose-range finding study in male and female Cynomolgus monkeys (Study DRF001). ADA-011 was administered by IV injection on Days 1 and 8 to Groups 1, 2 and 3 (2 males/1 female per group) at dose levels of 10, 30, and 100 mg/kg, respectively, and on Day 1 to Groups 4 and 5 (1 male/1 female per group) at dose levels of 1 and 3 mg/kg, respectively. Blood samples were obtained for Groups 1 - 3 at 0.083-, 2-, 7-, 24-, and 48-hours post-dose on Days 1 and 8, with additional timepoint collections 72-, 96-, and 168-hours post-dose on Day 1, only. Blood samples were obtained for Groups 4 and 5 at 0- (pre-dose), 0.083-, 2- , 7-, 24-, 48-, 96-, 168-, 336-, and 504-hours post-dose. No gender differences in PK parameters were observed in this study.

[0295] Animals that received lower doses of ADA-011 had rapid clearance with drug concentrations dropping below the LLOQ (0. 1 mg/mL) at timepoints beyond 24- and 168- hours post-dose in the 1 and 3 mg/kg dosing groups, respectively. This phenomenon is likely due to TMDD, resulting in increased clearance and non-linear PK at doses below the saturation level.

[0296] Average Cmax increased in a more than dose-proportional manner between doses of 1 to 10 mg/kg and in a slightly less than dose-proportional manner between doses of 10 to 100 mg/kg. Average AUCo-48 increased in a more than dose-proportional manner between doses of 1 to 10 mg/kg and a slightly less than dose-proportional manner between doses of 10 to 100 mg/kg.

[0297] Little to no accumulation in average C_max or AUCo-48h was observed after administration of a second dose at 10, 30, and 100 mg/kg. ADA-011 concentrations declined in a biphasic manner with average half-life estimates of 8.13-, 27-, 34.4-, 49.6- , and 45.8- hours after the first dose for dose levels of 1, 3, 10, 30, and 100 mg/kg, respectively. The half-life in the 1 and 3 mg/kg groups was shorter due the lack of measurable data beyond 24 and 168 hours, respectively, like due to TMDD

Toxicokinetics of ADA-011 After Repeat IV Dose Administration in Cynomolgus Monkeys

[0298] Toxicokinetic parameters of ADA-011 were evaluated as a part of the GLP, 4- week, repeat-dose toxicology study in male and female Cynomolgus monkeys (Study 20330080). ADA-011 was administered by IV injection once per week (Days 1, 8, 15, 22, and 29) or administered as a single dose on Day 1 according to the study design described previously. The results are provided in Table 15 below. All repeat-dose study animals were evaluated up to 24 hours after the fifth dose on Day 29, and recovery animals remained on-study until 672 hours (28 days) post-dose on Day 29.

[0299] Blood samples were obtained at 0- (pre-dose), 0.083-, 1-, 8-, 24-, 72-, and 120- hours post-dose on Day 1 ; at 0- (pre-dose) and 0.083-hours post-dose on Days 8 and 15; at 0- (pre-dose), 0.083-, 1-, 8-, 24-, and 72-hours post-dose on Day 22; and at 0- (predose), 0.083- and 24-hours post-dose for all animals. Additional samples were collected at 72-, 168-, 360-, 504-, and 672-hours post-dose for recovery animals. For single-dose animals, blood samples were obtained at 0- (pre-dose), 0.083-, 1-, 8-, 24-, 72-, 120-, 168- , 336-, 504-, at 672-hours post-dose. No measurable concentrations were observed in control animals and no gender differences were noted in this study.

Table 15. Study 20330080 Experimental Design

^:l Based on the most recent body weight measurement. ^b Groups 1-4 received dose administration once weekly for 5 doses onDays 1, 8, 15, 22 and 29. Group 5 received a single dose on Day 1. ^c Main Study animals from Groups 1-4 were euthanized on Day 31. Recovery animals were euthanized on Day 57. Group 5 animals were released from study on Day 31. ^d Group 5 animals were used for anti-drug antibody and toxicokinetic analysis.

[0300] Mean Cmax and AUCo-i68h values of ADA-011 increased with dose from 10 to 100 mg/kg on Days 1 to 22. On Day 1, exposure increased in a nearly dose-proportional manner between doses of 10 and 100 mg/kg. On Day 22, Cmax increased in an approximately dose-proportional manner across the tested dose range, but AUCo-i68h increased in an approximately dose-proportional manner between doses of 10 and 30 mg/kg and a more than dose-proportional manner between doses of 10 and 100 mg/kg and 30 and 100 mg/kg. The non-linear trend for AUCo-i68h values on Day 22 might result from an anti-ADA-011 immune response, resulting in decreased exposures at the lower doses.

[0301] The median time to maximum observed concentration (Tmax) value for ADA-011 was observed by 0.083 hours post-dose following dosing on Days 1 and 22 at all dose levels. Individual Tmax values for ADA-011 ranged from 0.083- to 24-hours post-dose at 10 mg/kg (both single- and repeat-dose) and ranged from 0.083- to 1-hour post-dose at 30 and 100 mg/kg.

[0302] No significant increase in systemic exposure was observed after repeat doses of ADA-011. Mean AUCo-i68h accumulation ratios were 0.533, 0.630, and 1.03 at 10, 30, and 100 mg/kg, respectively. Individual AUCo-i68h accumulation ratios ranged from 0.0281 to 1.27 at 10 mg/kg, from 0.210 to 0.972 at 30 mg/kg, and from 0.796 to 1.28 at 100 mg/kg. Accumulation ratios less than 1 are likely due to an anti-ADA-011 immune response following repeated dosing.

[0303] Concentrations declined in a biphasic manner with mean half-life values ranging from 33.9 to 53.7 hours following single administration (Day 1 for all doses) and from 14.3 to 32.9 hours following repeated administration. Mean volume of distribution ranged from 64.3 to 77.3 mL/kg following single administration of ADA-011 and from 38.5 to 53.5 mL/kg following repeated administration. Mean clearance values ranged from 1.19 to 7.62 mL/hr/kg following repeated administration. Mean AUCinf values following the first dose were 9810 (single dose), 11700, 30700, and 94400 hr*pg/mL at dose levels of 10 (single-dose), 10 (repeat-dose), 30, and 100 mg/kg, respectively.

Distribution

[0304] Monoclonal antibodies, such as ADA-011, are generally restricted to the central compartment as a result of molecule size. Thus, routine studies that assess distribution are not required per the ICH Guideline (ICH S6[R1 ] ) on Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals.

Metabolism

[0305]No specific studies were conducted to study ADA-011 metabolism as a classic drug metabolic elimination does not represent an important clearance mechanism for monoclonal antibodies. Monoclonal antibodies, such as ADA-011, are generally catabolized into small peptides, carbohydrates, and amino acids that are returned to the nutrient pool or excreted via the kidneys without any biological effects. Wang W, Wang EQ, Balthasar JP, Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther, 2008. 84(5): p. 548-558. Thus, in accordance with the ICH Guideline (ICH S6[R1]) on Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, no metabolism studies were conducted with ADA-011.

Excretion

[0306] Renal elimination is relatively unimportant for monoclonal antibodies as their large size limits the extent of glomerular filtration. Monoclonal antibodies, such as ADA-011, are generally catabolized into small peptides, carbohydrates, and amino acids that are returned to the nutrient pool or excreted via the kidneys without any biological effects. Thus, in accordance with the ICH Guideline (ICH S6[R1]) on Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, no excretion studies were conducted with ADA-011.

[0307] Pharmacokinetic drug interactions studies have not been conducted for ADA-011. In general, antibodies such as ADA-011 are not metabolized by cytochrome P450 (CYP450) enzymes or transported by P-glycoprotein (Pgp) or related ATP-binding cassette membrane transporters. Cytokines produced by activated lymphocytes may impact the levels of Pgp and the activity of CYP450 enzymes. Harvey RD, Morgan ET, Cancer, inflammation, and therapy: effects on cytochrome p450-mediated drug metabolism and implications for novel immunotherapeutic agents. Clin Pharmacol Ther, 2014. 96(4): p. 449-457. The clinical relevance of ADA-011 immune modulation and potential cytokine production that could impact Pgp and CYP450 is unknown, but a clinically relevant drug-drug interaction effect is considered highly unlikely. Thus, in accordance with guidelines and scientific evidence, no PK drug-drug interaction studies were conducted for ADA-011. USDHHS, CDER, CBER. Draft Guidance. Drug-drug interaction assessment for therapeutic proteins guidance for industry. 2020; Huang SM, Zhao H, Lee JI, Reynolds K, Zhang L, Temple R, et al., Therapeutic protein-drug interactions and implications for drug development. Clin Pharmacol Ther, 2010. 87(4): p. 497-503, Seitz K, Zhou H, Pharmacokinetic drug-drug interaction potentials for therapeutic monoclonal antibodies: reality check. J Clin Pharmacol, 2007. 47(9): p. 1104- 1118.

Translational PKPD Modeling

[0308] Exploratory population PK modeling was conducted based on Cynomolgus monkey data with the goal of extrapolating the PK parameters to humans. A two- compartment PK model with mixed linear and non-linear (Michaelis-Menten) clearance to approximate the effect of TMDD was chosen.

Human PK Projection

[0309] Body weights of 2 to 80 kg were used for Cynomolgus monkeys and humans, respectively to generate human PK projections. Projected ADA-011 PK exposure in patients following the first dose and projected ADA-011 safety margins in patients following the first dose are found in Table 16 and Table 17, respectively.

Table 16. Projected ADA-011 PK Exposure in Patients (First Dose)

AUCo-i68hr = area under the concentration time curve, hour zero to 168 hours; Cmax = maximum observed concentration; GLP = good laboratory practice; Q3W = every 3 weeks.

Table 17. Projected ADA-011 Safety Margins in Patients (First Dose)

AUCo-i68hr = area under the concentration time curve, hour zero to 168 hours; Cmax = maximum observed concentration; HNSTD = highest non-severely toxic dose; NOAEL = no-observed-adverse-effect level; Q3W = every 3 weeks. [0310] The safety profile of ADA-01 1 was evaluated in a 10-day non-GLP dose rangefinding tolerability and TK study and a 4-week GLP repeat-dose toxicology study in Cynomolgus monkeys administered once per week via IV injection. Local tolerance was evaluated as a part of the repeat-dose toxicity studies. Other nonclinical safety tests include a comprehensive assessment (non-GLP) of the potential for ADA-01 1 to elicit in cytokine release in human PBMCs and to promote ADCC, CDC, and ADCP activity. An overview of the ADA-01 1 nonclinical toxicology program is provided in Table 18.

Table 18. Summary of Toxicology Studies for ADA-011

ADCC = antibody-dependent cell-mediated cytotoxicity; ADCP = antibody-dependent cell-mediated phagocytosis; CDC = complement-dependent cytotoxicity; GLP = Good Laboratory Practice; HEK = human embryonic kidney; IV = intravenous; PBMC = peripheral blood mononuclear cell; TK = toxicokinetic.

Repeat Dose Toxicity:

10-Day Tolerability and TK Study of ADA-011 in Cynomolgus Monkeys

[0311] The objectives of this dose range-finding study were to evaluate the tolerability and TK of ADA-01 1 when administered by IV (slow bolus) inj ection once weekly to Cynomolgus monkeys on Days 1 and 8 for Groups 1 to 3 and once on Day 1 for Groups 4 and 5. [0312] The following parameters and endpoints were evaluated in this study: mortality, clinical observations, body weights (not collected post-dose for Groups 4 or 5), qualitative food consumption, clinical pathology parameters (hematology, coagulation, and clinical chemistry Groups 1 to 3), and macroscopic and microscopic examinations (Groups 1 to 3).

[0313] There were no ADA Oi l-related clinical signs or effects on qualitative food consumption. For the animals in Groups 1 to 3, there were no ADA-011 -related effects on body weights or definitive ADA 011 -related changes in clinical pathology. There were no ADA-011 -related macroscopic or microscopic findings.

[0314] In conclusion, administration of ADA-011 by IV (slow bolus) injection on Days 1 and 8 for Groups 1 to 3 and once on Day 1 for Groups 4 and 5 was well tolerated at all levels tested within the scope of this study (up to 100 mg/kg).

1-Month Repeat-Dose Toxicology Study of ADA 011 in Cynomolgus Monke s with a 4-Week Recovery Period

[0315] The objectives of this study were to determine the potential toxicity of ADA-011 in Cynomolgus monkeys dosed once weekly (Study Days 1, 8, 15, 22, and 29) by IV injection and to determine the potential reversibility of any findings through end of recovery (Study Day 57) (Study No. 20330080). An overview of study design is included in Table 15.

[0316] The following parameters and end points were evaluated in this study: mortality, clinical observations (cage side and post-dose), body weights, qualitative food consumption, ophthalmology, electrocardiology exams, clinical pathology parameters (hematology, coagulation, clinical chemistry, and urinalysis), bioanalysis and toxicokinetic parameters, anti-drug antibody evaluations, immunophenotyping, cytokines sample analysis, organ weights, and macroscopic and microscopic examinations.

[0317] All animals survived until their scheduled necropsy or until released to the testing facility animal colony. ADA-011 -related clinical signs were severe vomitus and decreased activity in one female at the 10 mg/kg dose. There were no ADA-011 -related effects on body weights, qualitative food consumption, hematology, coagulation, clinical chemistry, urinalysis, cytokines, organ weights, or macroscopic findings.

[0318] All ECGs evaluated in this study were qualitatively considered normal for Cynomolgus monkeys. Qualitative analysis included an evaluation of any abnormalities in rhythm, waveform morphology (for P, QRS, and T waves), or apparent functional changes. No abnormalities in rhythm were found. [0319] Administration of 10, 30, or 100 mg/kg ADA-011 resulted in dose-independent decreases in the absolute counts of CD159a⁺ NK cells, some of which reached statistical significance.

[0320] ADA-011 -related microscopic findings suggestive of drug immunogenicity were observed in individual animals at 30 and 100 mg/kg and included minimal perivascular mononuclear cell infiltrates in the spinal cord, sciatic nerve, and liver; minimal multifocal mononuclear cell infiltrates within the uvea of the eye; and/or minimal mixed cell infiltrates within the choroid plexus of the brain.

[0321] Preliminary findings concerning the development of anti-ADA-011 antibodies suggest impact on systemic exposure to ADA-011 resulting from anti-ADA-011 antibodies are more pronounced at lower dose levels.

[0322] In conclusion, administration of ADA-011 once weekly on Days 1, 8, 15, 22, and 29 for Groups 1 to 4 and once on Day 1 for Group 5 was well tolerated in Cynomolgus monkeys at dose levels of 10, 30, and 100 mg/kg. All animals survived for the interim study duration, and ADA-011-related findings were limited to immunophenotyping changes and cell infiltrates in multiple tissues. Based on the results under the conditions of this study, the no-observed-adverse-effect level (NOAEL) was determined to be 100 mg/kg.

Reproductive and Developmental Toxicity

[0323] Reproductive organs were examined microscopically as part of the GLP 1 -month toxicity and TK study in Cynomolgus monkeys. There were no findings of concern in these tissues.

Local Tolerance

[0324] Specifically designed local tolerance studies have not been conducted. The local effect of ADA-011 at the injection site was evaluated in the 10-day repeat dose toxicology study in Cynomolgus monkeys (Study No. 20282718). In the GLP 1 -month toxicology study in Cynomolgus monkeys, ADA-011 was administered once a week for 5 total administrations by IV injection at doses of 0, 10, 30, or 100 mg/kg/dose and did not produce any test article-related local irritation at the injection site(s) (Study No. 20330080).

Other Toxicity Studies

Effects of ADA-011 on Cytokine Release in Primary Human PBMCs

[0325] The objective of this study was to evaluate the potential of ADA-011 to trigger cytokine release in primary human PBMCs derived from ten (10) healthy donors (Study No. ADT02). PBMC samples were treated with varying doses of ADA-011 and response was compared to an anti-CD3 antibody (0KT3 clone) treatment (positive control), human IgGl isotype control antibody (negative control), and a no treatment control. Cytokine release by PBMCs was evaluated 24 hours following treatment in triplicate for all conditions.

[0326] ADA-011 did not induce a dose-dependent cytokine response for any of the cytokines tested. Soluble ADA-011 treatment resulted in release of IL-2, but this was only at some concentrations and was not consistent or dose-dependent. Similarly, there was a small increase in TNF-a in some donors and variable release of CCL4 or IL-6 will ADA-011 treatment, but these trends were not consistent across concentrations and donors.

Effects of ADA-011 on ADCC. ADCP, and CPC

[0327] Additional in vitro assays were performed to evaluate the mechanism of action associated with ADA-011. ADA-011 did not elicit any effect in ADCC assays using PBMCs, CDC assays using HEK293 cells, or ADCP assays using human macrophages. Clinical Information:

[0328] ADA Oi l has not been previously tested in a clinical setting. There are currently no approved or investigational products being developed in the U.S., or any other country that target all three LILRB1, 2, and 3 receptors.

[0329] Another anti-LILRB2 directed agent, MK-4830, is currently under investigation in a Phase 1 , open-label, first-in-human, multicenter study as monotherapy and in combination with pembrolizumab for patients with advanced solid tumors (NCT03564691). MK-4830 is a fully human monoclonal antibody specifically binding LILRB2, otherwise known as immunoglobin-like transcript 4, blocking its interaction with HLA-G and other ligands. Though MK-4830 specifically binds to LILRB2, compared to the broader binding of ADA-011 to LILRB1, 2, and 3 receptors, the safety results from this study provide information regarding the types of events that may occur following the administration of ADA-011. The primary objective of the Phase 1 clinical trial is to evaluate the safety and tolerability of MK-4830 as monotherapy and in combination with pembrolizumab. Siu LL, Wang D, Hilton J, Geva R, Rasco D, Perets R, et al., First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Clin Cancer Res, 2022. 28(1): p. 57-70. [0330] Subjects included in the monotherapy arm received escalating doses of IV MK- 4830 every 3 weeks with the following doses: 3 mg (n=2), 10 mg (n=2), 30 mg (n=l), 100 mg (n=7), 300 mg (n=8), 800 mg (n=15), and 1,600 mg (n=15). Subjects in the combination therapy group all received 200 mg pembrolizumab plus MK-4830 (IV every 3 weeks) at the following doses: 100 mg (n=5), 300 mg (n=6), 800 mg (n=8), and 1,600 mg (n=15). The reported median treatment duration was 1 month (range: 0-16) in the monotherapy arm and 4 months (range: 0—15) in the combination therapy arm.

[0331] The most common adverse events (> 20%) in the monotherapy arm (n=50) included fatigue, nausea, decreased appetite, and diarrhea. Adverse effects of any grade developed in 24 subjects (48%). Seven grade 3 or grade 4 events occurred in 3 subjects, including fatigue (n=l), increased AST (n=2), increased ALT (n=l), increased blood alkaline phosphatase (n=l), increased blood pressure (n=l), and increased gamma glutamyl transferase (n=l).

[0332] The most common adverse effects (> 20%) in the combination therapy arm (n=34) included decreased appetite, fatigue, and vomiting. Adverse effects of any grade developed in 28 patients (54%). Four subjects experienced a grade 3 or grade 4 event, including fatigue, pneumonitis, hyperglycemia, and hypotension.

[0333]No treatment-related deaths were reported in either treatment group. Moreover, no dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Summary of Data and Guidance for the Investigators:

Description

[0334] The ADA-011 drug product is formulated as a sterile, colorless to slightly yellow, clear to slightly opalescent sterile solution for infusion. The drug product is formulated at a target concentration of 25 mg/mL in 20 mM L-histidine/L-histidine monohydrochloride monohydrate buffer with 8% (w/v) sucrose and 0.015% (w/v) polysorbate 80, with pH 5.7. The labelled volume is 4 mL per vial and will be supplied in 10 mL glass vials.

Pharmacology, Toxicology, and Safety

Overview

[0335] A comprehensive series of nonclinical pharmacology, PK, and toxicology studies as well as clinical pharmacology and safety studies have been completed to support the clinical development of ADA-011 for the treatment of advanced solid tumors in adults.

Nonclinical [0336] The nonclinical data presented in the pharmacology, PK, and toxicology studies demonstrate a favorable safety profile of ADA-011 and suggest that robust safety margins exist over the proposed clinical doses for the treatment of advanced solid tumors in adults. The key findings of the ADA-01 1 pharmacodynamic studies are as follows:

• ADA011 binds human LILRB1, LILRB2, and LILRB3 with low nM affinity and has 3- fold weaker affinity for LILRA1 and LILRA3. Similar binding affinity is observed to LILRs found in Cynomolgus monkeys. ADA011 does not bind Fc receptors or Clq.

• ADA-011 binds LILRs found on human immune cells in vitro. ADA-011 binding promotes immune activation (including macrophage activation and NK cell-mediated cy totoxicity) in in vitro co-culture assays.

• ADA-01 1 does not induce dose-dependent cytokine responses in ex vivo assays using human PBMCs.

• ADA-011 promotes an immune-mediated anti-tumor response in chondrosarcoma and liver cancer cell models in vivo.

[0337] The safety pharmacology program characterized the potential CNS and CV effects of ADA-01 1 as a part of the 4-week, repeat-dose, GLP study in Cynomolgus monkeys and determined that ADA Oi l did not have effects on any of these organ systems at the 10, 30, or 100 mg/kg dose levels.

[0338] PK and TK studies were conducted in mice and Cynomolgus monkeys to determine PK parameters associated with ADA-011. The key findings of these studies were:

• ELISA and ECL methods were validated for evaluating ADA-011 binding in mice and Cynomolgus monkeys, respectively.

• In a non-GLP, single-dose study in female BALB/c SCID mice dosed with 3, 10, and 30 mg/kg ADA011 by IP injection, average Cmax increased in a less than doseproportional manner between doses of 3 and 10 mg/kg and in a more than doseproportional manner between doses of 3 to 30 mg/kg and 10 to 30 mg/kg. Average AUCiast was nearly dose-proportional across the three tested dose levels. Average T1/2 ranged from 192 hours to 316 hours across the tested dose range.

• In a 4-week, repeat-dose, GLP study in Cynomolgus monkeys dosed with 10, 30, and 100 mg/kg once weekly, Cmax increased in an approximately dose-proportional manner across the tested range on Days 1 and 22. AUCo-i68h increased in an approximately dose proportional manner on Day 1 but had a non-linear trend on Day 22, which is likely the result of an anti-ADA-011 immune response at lower dose levels. No significant increases in system exposure were observed after repeat doses of ADA-011 and no gender differences were observed in any studies completed in Cynomolgus monkeys.

[0339] Repeat-dose toxicology studies of ADA Oi l following IV injection in Cynomolgus monkeys were conducted. The key findings of these studies are:

• In the 10-day, repeat-dose, non-GLP, repeat-dose and TK study in Cynomolgus monkeys, ADA-01 1 was well-tolerated up 100 mg/kg dosing on Days 1 and 8. No clinical signs, changes in qualitative food consumption, effects on body weight, or macroscopic or microscopic changes in clinical pathology were observed.

• In the 4-week, repeat-dose, GLP toxicology study, weekly IV injection of ADA-011 was tolerated up to the highest dose level (100 mg/kg). ADA-011 results in no mortality, or effects on body weights, qualitative food consumption, heart rhythm, hematology, coagulation, clinical chemistry, urinalysis, cytokines, organ weights, or macroscopic findings. ADA-011 -related clinical signs were severe vomiting and decreased activity at the 10 mg/kg dose. Microscopic signs of drug immunogenicity were observed at the 30 and 100 mg/kg doses.

• Observation of Cynomolgus monkeys for 4 weeks following weekly dosing of 100 mg/kg determined that ADA-011 -induced effects were reversible.

• Based on findings from the pivotal GLP study in Cynomolgus monkeys, the NOAEL was determined to be 100 mg/kg. Thus, robust safety margins exist to support the current proposed clinical doses of ADA-011 for the treatment of advanced solid tumors in adults.

[0340] Local tolerance was assessed as a part of the toxicology studies, and it was determined that ADA-01 1 injections did not produce any test article-related irritation at injection sites. Additional toxicity studies determined ADA-01 1 does not induce dosedependent cytokine response in assays using human PBMCs and does not induce ADCC, ADCP, or CDC.

Clinical

[0341] The Phase 1 trial ADA-01 1-001 will be a first-in-human study, as no clinical trials have been performed with the ADA-01 1 antibody. Clinical Studies and Target Indications:

[0342] Protocol ADA-011-001 describes the planned first-in-human trial with ADA-011, which was designed to be a Phase 1, open-label, nonrandomized, multicenter, dose escalation with expansion trial of ADA-011 as monotherapy and in combination with pembrolizumab in subjects with advanced solid tumors.

Potential Adverse Events

[0343] There is no information from human studies regarding prior adverse events associated with the use of ADA-011, and Study ADA 011-001 is the initial clinical trial for ADA Oi l. Preclinical toxicology studies showed only a single animal at a single timepoint experienced severe vomiting and decreased activity (reported at the 10 mg/kg dose level in the 4-week, repeat-dose, GLP study in a single Cynomolgus monkey). No other clinical signs or abnormal laboratory findings were reported in any of the other animals at any other dose level, in this or other nonclinical studies.

[0344] Subjects should be closely monitored for early signs and symptoms indicative of infusion-related reactions (IRRs) and in the event of a suspected IRR, the ADA 011 infusion should be interrupted immediately. Trained clinical personnel should be prepared to intervene in the event of IRRs. Detailed instructions for management of IRRs are provided in the ADA 011-001 Protocol.

[0345] Cytokine release syndrome (CRS) may occur with immune-based therapies and may occur within minutes up to hours after the start of treatment and is most pronounced during the initial 72 hours of therapy. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation. Trained clinical personnel should be prepared to intervene in the event of CRS. Resources necessary for resuscitation should be readily available. CRS may be managed by administration of glucocorticoids, tocilizumab, siltuximab, anakinra. Detailed instructions for grading and management of CRS are provided in the ADA 011-001 Protocol.

[0346] Based on the experience of other immuno-oncology agents, ADA 011 may be associated with immune-related adverse events (irAEs). Therefore, subjects should receive treatment with ADA-011 at a site that has experience administering immunotherapies. Early recognition and management of irAEs may mitigate severe toxicity. Investigators should monitor subjects closely for potential irAEs, which may manifest after weeks of treatment, at the earliest. Detailed instructions for the management of irAEs are provided in the ADA-011-001 Protocol. Immune-related AEs may include neurological, dermatological, gastrointestinal, pulmonary, hepatic, endocrine, or renal AEs. In patients receiving combinations of ICIs, irAEs may occur earlier and at a higher grade.

Contraindications :

[0347]No reproductive toxicity studies with ADA Oi l have been performed in animals. Women of childbearing potential and men receiving ADA 011 must use a highly effective method of contraception. Pregnant, lactating, or breastfeeding women should not receive ADA Oi l or pembrolizumab.

[0348] Patients with known allergies or hypersensitivities to any of the active or inactive components of the ADA Oi l drug product should not be treated.

[0349] Patients with a history, risk of, or currently active autoimmune disease should not be treated with ADA Oi l.

[0350] Patients who had a prior solid organ transplant or allogenic hematopoietic stem cell transplant should not be treated with ADA Oi l .

Warnings and Precautions:

[0351] ADA-011 is an investigational product that should only be used under the terms defined in the clinical protocol associated with this Investigator’s Brochure. There is no information regarding the use of ADA-011 in humans from prior studies, as Study ADA-011-001 is the initial clinical trial.

Product Interactions

[0352] As discussed above, a clinically relevant drug-drug interaction effect is considered highly unlikely. Studies that examine the interaction between ADA-011 and other products have not been conducted in accordance with guidelines and scientific evidence. Use in Specific Populations

[0353] There is no clinical information available regarding the use of ADA 011 in specific populations.

Overdose:

[0354] There is no clinical information available regarding overdose with ADA-011. The risk of an overdose is low due to inpatient administration in a healthcare setting.

[0355] The NOAEL in Cynomolgus monkeys is 100 mg/kg based on the nonclinical toxicology studies. Doses higher than 100 mg/kg have not been studied. Based on the NOAEL and nearly identical binding affinity of ADA Oi l between human and Cynomolgus monkeys, the human equivalent dose is approximately 100 mg/kg. Based on the standard criteria used for determining the starting dose of anticancer drugs following the ICH S9 guideline, the maximum permitted starting dose in cancer patients is l/6th x 100 mg/kg with an additional safety factor of 10, or 1.67 mg/kg or 133.6 mg/patient administered weekly. The proposed starting dose of 20 mg (0.3 mg/kg) is 6.68 x lower than the dose supported by the NOAEL determined in the GLP toxicology study.

[0356] There is no antidote to ADA-011. Thus, in case of an overdose the subject should receive supportive care according to local guidelines, and potential side effects of ADA- 011 should be treated symptomatically.

Dosage and Administration:

[0357] The dose and dosing regimen for ADA 011 have not been previously evaluated.

[0358] The proposed starting dose of 20 mg (0.3 mg/kg) is 1.22 to 3.33 times lower than the dose calculated based on binding to PBMCs and B cells and approximately 6.68 times lower than the dose supported by the GLP toxicology study. The proposed starting dose is higher than the dose calculated based on binding of 9C9.E6 to extracellular domains of LILRB2 and ADA-011 binding to monocytes; however, these are static systems that are not expected to represent an open dynamic system. In the 4-week, repeat-dose, GLP toxicology study in Cynomolgus monkeys, systemic exposure (Cmax and AUCo-i68h) to ADA-011 on Day 1 at the NOAEL was 2590 pg/mL and 88200 hr*pg/mL, respectively, sexes combined. The exposure margin based on Cmax and AUCo-i68 at the NOAEL is 470- and 903-fold, respectively, relative to the projected exposure (Cmax of 4.59 pg/mL and AUCo-i68h of 97.7 hr*pg/mL) at the 20 mg (0.3 mg/kg) clinical starting dose (Table 5- 10). To be able to fully characterize the safety, PK, and PD, Adanate is proposing a starting dose of 20 mg administered IV every 3 weeks.

[0359] The planned doses of ADA-011 for Study ADA-011-001 in the monotherapy dose escalation part will range from 20 mg IV every 3 weeks to 2400 mg IV every 3 weeks. Following the completion of the monotherapy dose escalation part and the determination of a maximum tolerated dose or recommended Phase 2 dose, the combination of ADA 011 and pembrolizumab will be evaluated with a 3+3 dose escalation scheme. The starting dose for combination therapy will be below the monotherapy maximum tolerated dose or recommended Phase 2 dose as determined in the monotherapy dose escalation part of the trial.

Supply, Storage, and Handling

[0360] ADA-011 sterile solution for infusion is supplied in a colorless borosilicate glass vial, with flip-off seals over grey rubber stoppers. The clinical trial material must be kept in a locked area with limited access under refrigerated controlled temperature conditions (between 2°C and 8°C). Upon dilution with normal saline (0.9% sodium chloride), the prepared dose can be stored at room temperature under ambient illumination for up to 4 hours (inclusive of administration time).

[0361] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the instant disclosure. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the embodiments disclosed herein, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

SEQUENCES

Claims

CLAIMS Listing of Claims

1. An anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof comprising:

(b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120;

(c) a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130;

(f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160.

2. An anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof comprising:

3. An anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310; (b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340;

(e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350; and/or

4. An anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410;

(b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420;

(f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460.

5. An anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510;

(b) a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520;

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540; (e) a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550; and/or

(f) a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

6. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-5, wherein the anti-LILRB antibody or LILRB binding fragment thereof binds to LILRB I, LILRB2, and/or LILRB3.

7. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-6, wherein the anti-LILRB antibody or antigen binding fragment thereof binds to a combination of LILRB 1 and LILRB2, LILRRB1 and LILRB3, and/or LILRB2 and LILRB3.

8. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-7, wherein the anti-LILRB antibody or antigen binding fragment thereof binds to LILRB1, LILRB2, and LILRB3.

9. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-8, comprising: a heavy chain framework region 1 (H-FR1), a heavy chain framework region 2 (H- FR2), a heavy chain framework region 3 (H-FR3), and a heavy chain framework region 4 (H-FR4); and a light chain framework region 1 (L-FR1), a light chain framework region 2 (L- FR2), a light chain framework region 3 (L-FR3), and a light chain framework region 4 (L-FR4).

10. The anti-LILRB antibody or LILRB binding fragment thereof of claim 9, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises: the H-FR1, the H-FR2, the H-FR3, and the H-FR4 comprise an amino acid sequence having at least about 70% identity to the H-FR1, the H-FR2, the H-FR3, and the H-FR4 of any one of SEQ ID NOs: 101 or 170-173; and/or the L-FR1, L-FR2, L-FR3, and L-FR4 comprise an amino acid sequence having at least about 70% identity to the L-FR1, the L-FR2, the L-FR3, and the L-FR4 of any one of SEQ ID NOs: 102 or 180-183.

11. The anti-LILRB antibody or LILRB binding fragment thereof of claim 10, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises: the H-FR1, the H-FR2, the H-FR3, and the H-FR4 comprise an amino acid sequence of the H-FR1, the H-FR2, the H-FR3, and the H-FR4 of SEQ ID NOs: 101 or 170-173; and/or the L-FR1, L-FR2, L-FR3, and L-FR4 comprise an amino acid sequence of the L- FR1, the L-FR2, the L-FR3, and the L-FR4 of SEQ ID NOs: 102 or 180-183.

12. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-11, comprising: a heavy chain variable region comprising the H-CDR1, H-CDR2, and H-CDR3; and/or a light chain variable region comprising the L-CDR1, L-CDR2, and L-CDR3.

13. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 101; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 102.

14. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 101 ; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 102.

15. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an ammo acid sequence having at least about 70% identity to SEQ ID NO: 201; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 202.

16. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 201 ; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 202.

17. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an ammo acid sequence having at least about 70% identity to SEQ ID NO: 301; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 302.

18. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 301 ; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 302.

19. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 401; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 402.

20. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 401 ; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 402.

21. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 501; and/or the light chain variable region comprises an amino acid sequence having at least about 70% identity to SEQ ID NO: 502.

22. The anti-LILRB antibody or LILRB binding fragment thereof of claim 12, wherein: the heavy chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 501 ; and/or the light chain variable region comprises an amino acid sequence set forth in SEQ ID NO: 502.

23. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1 to 22, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region.

24. The anti-LILRB antibody or LILRB binding fragment thereof of claim 23, wherein the reduced effector function is selected from the list consisting of reduced antibodydependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof.

25. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 23 to 24, wherein the variant Fc region comprises SEQ ID NO: 105.

26. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1 to 25, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 103 and the light chain comprises SEQ ID NO: 104.

27. An anti-LILRB antibody or LILRB binding fragment thereof comprising a heavy chain variable region polypeptide, the heavy chain variable region polypeptide comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1 ) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, and/or a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130;

28. An anti-LILRB antibody or LILRB binding fragment thereof comprising a light chain variable region polypeptide, the light chain variable region comprising:

(d) a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440. a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or

29. A composition comprising an immune cell and an anti-leukocyte immunoglobulin- like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB3.

30. The composition of claim 29, where the immune is a monocyte or lymphocyte.

31. The composition of claim 29, wherein the immune cell is selected from the group consisting of: (i) a T cell, (ii) a B cell, (iii) an NK cell, (iv) a macrophage, and (v) any combination of the T cell, the B cell, the NK cell, and the macrophage.

32. A composition comprising a plurality of cells and an anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB3, the plurality of cells comprising one or more immune cells.

33. The composition of claim 32, wherein the one or more immune cells are selected from the group consisting of: (i) monocytes, (ii) lymphocytes, and (iii) both monocytes and lymphocytes.

34. The composition of claim 32, wherein the one or more immune cells are selected from the group consisting of: (i) T cells, (ii) B cells, (iii) NK cells, (iv) macrophages, and (v) any combination of T cells, B cells, NK cells, and macrophages.

35. The composition of any one of claims 33 to 34, wherein the plurality of cells are obtained from an individual.

36. The composition of any one of claims 33 to 34, wherein the plurality of cells are within or derived from a blood sample or a PBMC sample.

37. The composition of any one of claims 29 to 36, wherein the anti-leukocyte immunoglobulin-like receptor subfamily B (LILRB) antibody or LILRB binding fragment thereof binds LILRB1, LILRB2, and LILRB3 in an ELISA.

38. The composition of any one of claims 29 to 37, wherein the anti-LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB I, LILRB2, and LILRB3 in an ELISA with a reference antibody comprising:

(a) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 110, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 120, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 130, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 140, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 150, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 160;

(b) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260;

(c) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 310, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 320, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 330, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 340, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 350, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 360;

(d) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 410, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 420, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 430, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 440, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 450, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 460; or

(e) a heavy chain complementarity determining region 1 (H-CDR1) comprising an ammo acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

39. The composition of any one of claims 29 to 37, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises the anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1 to 25.

40. A method of inhibiting and/or preventing an interaction between a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) molecule and a major histocompatibility complex class I (HLA) molecule, the method comprising contacting the LILRB2 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, and LILRB3.

41. A method of inhibiting and/or preventing an interaction between a leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) molecule and a major histocompatibility complex class I (HLA) molecule, the method comprising contacting the LILRB1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB3.

42. A method of inhibiting and/or preventing an interaction between a leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) molecule or a LILRB2 molecule and a major histocompatibility complex class I (HLA) molecule, the method comprising contacting the LILRB 1 molecule or the LILRB2 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB3

43. The method of any one of claims 40 to 42, wherein the inhibiting and/or preventing is measure by an ELISA or cell binding assay.

44. The method of any one of claims 40 to 43, wherein the a major histocompatibility complex, class I protein is selected from the list consisting of: (i) HLA-G, (ii) HLA- A, and (iii) both HLA-G and HLA- A.

45. A method of modulating leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) expressed on the surface of a cell, the method comprising contacting the LILRB2 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1, LILRB2, and LILRB3.

46. A method of modulating leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB 1) expressed on the surface of a cell, the method comprising contacting the LILRB 1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB1 , LILRB2, and LILRB3.

47. A method of modulating leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3) expressed on the surface of a cell, the method comprising contacting the LILRB 1 molecule with an anti-LILRB antibody or LILRB binding fragment thereof that binds LILRB 1, LILRB2, and LILRB3.

48. The method of any one of claims 40 to 47, wherein the LILRB 1 or LILRB2 is expressed on the surface of a cell.

49. The method of claim 48, wherein the cell is an immune cell.

50. The method of claim 49, wherein the immune cell is selected from the group consisting of: (i) a monocyte, (ii) a lymphocyte, and (iii) both the monocyte and lymphocyte.

51. The method of claim 48, wherein the cell is selected from the group consisting of: (i) a T cell, (ii) a B cell, (iii) an NK cell, (iv) a macrophage, and (v) any combination of the T cell, the B cell, the NK cell, and the macrophage.

52. The method of any one of claims 37 to 45, wherein the cell is in an individual.

53. The method of claim 52, wherein the individual has a tumor.

54. The method of claim 53, wherein the tumor is a solid tumor.

55. The method of any one of claims 40 to 54, wherein the anti-LILRB antibody or

LILRB binding fragment thereof binds LILRB1, LILRB2, and LILRB3 in an ELISA.

56. The method of any one of claims 40 to 55, wherein the anti-LILRB antibody or LILRB binding fragment thereof competes for binding to LILRB 1, LILRB2, and LILRB3 in an ELISA with a reference antibody comprising:

57. The method of any one of claims 40 to 56, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises:

(b) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 210, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 220, a heavy chain complementarity determining region 3 (H-CDR3) comprising an ammo acid sequence set forth in SEQ ID NO: 230, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 240, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 250, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 260;

(e) a heavy chain complementarity determining region 1 (H-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 510, a heavy chain complementarity determining region 2 (H-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 520, a heavy chain complementarity determining region 3 (H-CDR3) comprising an ammo acid sequence set forth in SEQ ID NO: 530, a light chain complementarity determining region 1 (L-CDR1) comprising an amino acid sequence set forth in SEQ ID NO: 540, a light chain complementarity determining region 2 (L-CDR2) comprising an amino acid sequence set forth in SEQ ID NO: 550, and/or a light chain complementarity determining region 3 (L- CDR3) comprising an amino acid sequence set forth in SEQ ID NO: 560.

58. The method of any one of claims 40 to 57, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises the anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1 to 28.

59. The method of any one of claims 40 to 58, wherein the anti-LILRB antibody or LILRB binding fragment thereof comprises a variant Fc region comprising one or more mutations relative to a wildtype Fc region, wherein the variant Fc region exhibits reduced effector function compared to the wildtype Fc region.

60. The method of claim 59, wherein the reduced effector function is selected from the list consisting of reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced complement mediated cytotoxicity (CDC), reduced affinity for Clq, and any combination thereof.

61. The method of any one of claims 59 to 60, wherein the variant Fc region comprises SEQ ID NO: 105

62. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-5, wherein the anti-LILRB antibody or LILRB binding fragment thereof binds to LILRB1, LILRB2, LIRB3, and/or LILRB5.

63. The anti-LILRB antibody or LILRB binding fragment thereof of any one of claims 1-5, wherein the anti-LILRB antibody or LILRB binding fragment thereof binds to LILRB5.

64. The method of any one of claims 40 to 54, wherein the anti-LILRB antibody or LILRB binding fragment thereof binds LILRB1, LILRB2, LILRB3, and/or LILRB5.

65. The method of any one of claims 40 to 54, wherein the anti-LILRB antibody or

LILRB binding fragment thereof binds LILRB5.